Mammals have evolved complex genetic programmes that
regulate the development and function of immune cells,
and enable the immune system to mount specific responses
against invading foreign pathogens while maintaining tol-
erance to self. Aberrant regulation of the immune system
leads to various immune-related pathological disorders,
such as autoimmune diseases and leukaemias. Previous
studies have revealed a wealth of knowledge about the
complex transcriptional programmes that regulate the
expression and function of various growth factors, cell-
surface receptors, intracellular signalling molecules
and transcription factors, which have a central role in
maintaining the equilibrium and function of vertebrate
immune systems. However, little is known about the role
of post-transcriptional regulation of gene expression in the
development and function of immune cells. Interestingly,
recent discoveries have revealed the existence of poten-
tially widespread regulatory mechanisms that function
at a post-transcriptional level and that have crucial roles
in animal development. The mediators of these processes
are known as microRNAs (miRNAs) — an abundant class
of endogenous small non-coding RNAs of approximately
22 nucleotides in length that can regulate gene expression
post-transcriptionally by affecting the degradation and
translation of target mRNAs (reviewed in REFS 1–3). This
Review focuses on the mechanisms by which miRNAs
regulate gene expression and provides an overview of the
important and diverse roles of individual miRNAs in the
vertebrate immune system and in host–viral interactions.
Presence of abundant miRNA genes in animals
The discovery of lin‑4 and let‑7, which are the proto-
type miRNA genes in Caenorhabditis elegans, and their
functional characterization led to the suggestion that
animal genomes might also contain lin‑4- and let‑7-like
non-coding RNA genes that control gene expression at
post-transcriptional levels4–8. The lin‑4 and let‑7 genes
each produces a mature miRNA of ~22 nucleotides
in length that is processed from a stem-loop precursor
miRNA (pre-miRNA) of ~60 nucleotides in length. It is
thought that lin-4 and let-7 mature miRNAs can form
imperfect Watson–Crick base pairs at multiple sites within
the 3′ untranslated region (UTR) of their cognate mRNA
targets, the lin‑14 and lin‑41 mRNAs, respectively, to
repress their expression at the post-transcriptional level.
So far, only a few miRNA genes have been identified
using forward genetics approaches, including the lin‑4,
let‑7 and lsy‑6 genes in C. elegans, and the Bantam and
mir‑14 genes in Drosophila melanogaster4,5,9–11. A large
number of endogenous mature lin-4 - and let-7-like
small RNAs were identified through deliberate clon-
ing of small RNAs from multiple animal species or
through computational predictions12–20. These compu-
tational predictions suggested that the human genome
might encode as few as one thousand pre-miRNAs
to as many as tens of thousands pre-miRNAs18,19,21.
This figure range is much higher than the number of
miRNA genes that have been identified to date by clon-
ing20,22,23. Interestingly, some functional miRNA genes
(such as lsy‑6) seem to produce extremely low levels
of mature miRNA, as indicated by high-throughput
sequencing analyses23, which suggests that high levels
of mature miRNAs might not be necessary for the effi-
cient function of some miRNA genes. If there are many
lsy‑6-like miRNA genes that produce low levels of
mature miRNA, but yet still function efficiently, then
*Whitehead Institute for
Biomedical Research and
Department of Biology,
Massachusetts Institute of
Technology, Nine Cambridge
Massachusetts 02142, USA.
‡Department of Microbiology
and Immunology, Baxter
Laboratory of Genetic
University School of Medicine,
269 Campus Drive, CCSR
3205, Stanford, California
C.‑Z.C. and H.F.L.
21 January 2008
A classical genetic analysis
approach that proceeds from
phenotype to genotype by
positional cloning or candidate-
Micromanagement of the immune
system by microRNAs
Harvey F. Lodish*, Beiyan Zhou*, Gwen Liu‡ and Chang‑Zheng Chen‡
Abstract | MicroRNAs (miRNAs) are an abundant class of evolutionarily conserved small
non-coding RNAs that are thought to control gene expression by targeting mRNAs for
degradation or translational repression. Emerging evidence suggests that miRNA-mediated
gene regulation represents a fundamental layer of genetic programmes at the post-
transcriptional level and has diverse functional roles in animals. Here, we provide an
overview of the mechanisms by which miRNAs regulate gene expression, with specific focus
on the role of miRNAs in regulating the development of immune cells and in modulating
innate and adaptive immune responses.
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|||||| ||| ||||||||||||||||
CACCCU UUC UCAUCUGACAUAUCAA C
G - UG UAGAGGUUCUAC
GUCCC UUCCGUCAUCCAACAUAUCAA U
||||| ||| |||||||||||||||| C
AUCCU UUC UCAUCUAACAUAUCAA A
- UG UAGAGGGUCACC
||| ||| ||| ||||||||||||| | | C
UCC UUC AUC UCCGACAUGUCAA A G A
-U G C --UAG GG A
||| ||| |||||||||||||||| |||||| C
UCC UUC UCAUCUAACAUAUCAA GUCCCG
U UG UAGGGUAUC U
|| |||||| ||| ||| ||||||||||||| || | | C
CG AGGUUC UUC AUC UCCAACAUGUCAA UU A G C
- CU G U -- G GG U
||||||| |||||||||||||| |||||
GGAUUCU UUCCGUCGUCCAGC UAUCA U
- A AUGGAGGAACACCCG
|| ||| ||| |||||||||||||||| C
GG CCC UUC AUCCUCCGGCAUAUCA C
A CU G CUAGAGGAAC
|||| | |||||||||||||||||||||| ||||||| A
AGUC C UCCGUUAUCUAACAUAUCAAUA UCCCAUU U
- CU GAGGACUUG U
||| |||||||| |||||||||||| |||| || ||||
CCG UUCCGUCA CGGACAUGUCAA UAGA AC AUGG C
A - C ----- GG - C
|| ||||||||||||| |||||||||||||| ||
AC AGGCCAUUCCAUC UUUAACGUAUCAAG CC U
G AG U UGG ACCA
|||| ||||||||||||||||| ||| || ||||| A
AUCG UUCCGUCAUCGAACGCG CAA UC GCCCG C
- U UAGAGGUG - UUA
Nature Reviews | Immunology
UGGGA GAG AGUAGGUUGUAUAGUU C
UU G U
AGG GAG UAG AGGUUGUAUAGUU U C U
UAGAA UA A
GGG GAG AGUAGGUUGUAUAGUU UGGGGC
CGGGG GAGGUAGUAGGUUGUGUGGUU U
A UU G U
GC UCCGGG GAG UAG AGGUUGUAUGGUU GA U C C
UA G UA A
CCUAGGA GAGGUAGUAGGUUG AUAGU U
C CU G
CC GGG GAG UAGGAGGUUGUAUAGU A
UCAG G AGGUAGUAGAUUGUAUAGUUGU GGGGUAG G
GUGGGA GAG AGUAGAUUGUAUAGUU C
GGC GAGGUAGU GUUUGUACAGUU GUCU UG UACC C
UGAGG -A A A
UG UCCGGUGAGGUAG AGGUUGUAUAGUUU GG U
UGGC GAGGUAGUAGUUUGUGC GUU GG CGGGU G
-------- U UGU
a Mature let-7 miRNAs
b Pre-let-7 miRNAs
c Primary miRNA transcripts
Caenorhabditis elegansCaenorhabditis elegans
Homo sapiensHomo sapiens
it is possible that the number of miRNA genes could
be on the high side of current estimates.
It is also important to note that known miRNAs
can be classified into large families that comprise
members that encode closely related mature miRNA
sequences, often differing only by one or two nucleo-
tides. for example, in the human genome there are
11 let‑7 miRNA genes that produce 8 types of slightly
different mature let-7 miRNA (FIG. 1a). The product of
one of the human let‑7 miRNA genes let-7i regulates
Toll-like receptor 4 (TlR4) expression and contributes
to cholangiocyte (human biliary epithelial cells)
immune responses against Cryptosporidium parvum
infection24. Interestingly, the conservation of miRNA
gene family members is often limited to the mature
miRNA sequences of ~22-nucleotide in length but
not to the sequences flanking the pre-miRNAs and
pre-miRNA stem-loops (FIG. 1a,b)25. These observ-
ations suggest that some miRNA genes evolved by
gene duplication and by varying the pre-miRNA
flanking and stem-loop sequences22,26. finally, many
pre-miRNA stem-loops are clustered in the genome
Figure 1 | MicroRNAs (miRNAs) and miRNA genes. a | Sequence alignment of Caenorhabditis elegans and Homo
sapiens mature let-7 miRNA family members. Of interest to this article, it has been recently shown that let-7i
regulates Toll-like receptor 4 expression and contributes to cholangiocyte (human biliary epithelial cells) immune
responses against Cryptosporidium parvum infection24. It is not yet known if miRNA genes that produce nearly
identical mature miRNAs, such as the let-7 miRNA family members, have the same activity in biological assays.
b | Predicted stem-loop structures containing the C. elegans and H. sapiens mature let-7 miRNAs family members.
Mature miRNA sequences are indicated in red. c | Representation of primary miRNA transcripts with one (top) or
two (bottom) precursor miRNA(s).
NATURe RevIeWS | iMMuNology
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Nature Reviews | Immunology
Primary miRNA transcript
(RISC). A multi-protein small
interfering RNA (siRNA)
complex that binds short
antisense RNA strands and
guides the cleavage of target
RNAs. This complex is thought
to be important for post-
transcriptional gene regulation
by siRNAs and microRNAs.
(FIG. 1c) and may be co-transcribed and processed into
multiple mature miRNAs25. However, it has not been
tested whether miRNA genes that produce nearly iden-
tical mature miRNAs, such as the let-7 family of miRNAs
(FIG. 1), have the same activity in biological assays.
The biogenesis of mature miRNAs
Mature miRNAs are produced from long primary
transcripts that contain the pre-miRNA, through a
series of endonucleolytic maturation steps27 (FIG. 2).
Some primary miRNA transcripts are made by RNA
polymerase II and have 5′ caps and 3′ poly(A) tails28,29,
whereas others are transcribed by RNA polymerase III
(REF. 30). In the canonical pathway of miRNA biogenesis,
long primary miRNA transcripts are processed into
corresponding pre-miRNA stem-loops of ~60 nucleotides
in length by the nuclear-specific ‘microprocessor’ com-
plex that is comprised of the RNase III enzyme Drosha
and its partner DGCR8 (DiGeorge syndrome critical
region gene 8; known as Pasha in D. melanogaster)31–34.
In D. melanogaster, however, some intronic miRNA
precursors, termed ‘Mitrons’, are processed in the
nucleus by the usual RNA splicing machinery and not
by the Drosha endonuclease35,36. In either case, the pre-
miRNAs are then actively transported to the cytoplasm
by exportin-5 in a RAS-related nuclear protein–guanosine
triphosphate (RAN–GTP)-dependent manner and are
further processed into ~22-nucleotide duplexes by the
cytoplasmic RNase III enzyme Dicer37–42. The func-
tional miRNA strand is then selectively loaded into the
RNA-induced silencing complex (RISC)43,44. As indicated
by miRNA cloning analyses22, the RISC-loading process
is often asymmetric in that a small RNA (~22 nucleo-
tides) corresponding to only one side of the miRNA
stem-loop precursor is preferentially incorporated,
whereas the complementary strand (miR*) may be
degraded. The information for the sequential process-
ing, maturation and RISC loading of miRNAs is likely
to be encoded in the sequences of the primary and pre-
miRNAs. based on this assumption, when expressing
an miRNA for experimental purposes, it is probably
necessary to include the corresponding genomic flank-
ing sequences of that miRNA to ensure proper miRNA
processing and maturation45–49. Mature miRNA expres-
sion may be regulated at various stages of biogenesis.
The relative ratio of mature miRNA to pre-miRNA can
change depending on the tissue, which indicates that
regulation occurs at the post-transcriptional level50,51,
although it is unclear what the biological relevance and
mechanisms might be for such regulation.
Mechanisms of action of miRNAs
The end result of miRNA-mediated gene regulation is
clearly a reduction in the total amount of target protein
that is produced; however, the fate of most mRNAs
that are targeted by miRNAs remains unclear. In some
cases, miRNAs have been shown to repress target gene
expression at the translational level, with mRNA levels
remaining constant and the level of the encoded pro-
tein declining, whereas in other cases, miRNAs repress
target gene expression by triggering the degradation
of target mRNAs (reviewed in REF. 52). for example,
using DNA microarray analysis, lim et al. found that
transfected miRNAs induce the degradation of a large
number of mRNAs that contain putative miRNA bind-
ing sites53. Nevertheless, it is still unclear how miRNAs
mediate target gene repression.
However, a number of mechanisms are emerging by
which miRNAs can inhibit translation54,55. miRNAs can
inhibit either the initiation or the post-initiation (elon-
gation) stages of protein translation. early studies in
C. elegans showed that lin-4 miRNA represses the lin‑14
and lin‑28 mRNAs at a step following the initiation of
mRNA translation56,57. Moreover, polysome profile analy-
ses of human cells showed that endogenous miRNAs are
associated with translating polysomes58,59. This analyses
Figure 2 | MicroRNA biogenesis and function in animal cells. Animal genomes have
specific genes that encode microRNAs (miRNAs). miRNA genes encode long primary
mRNA transcripts that in turn produce mature miRNAs through a series of
endonucleolytic maturation steps that are thought to be essential for the production
of functional miRNAs. Primary miRNA transcripts are processed into precursor miRNA
(pre-miRNA) stem-loops of ~60 nucleotides in length by the nuclear RNase III enzyme
Drosha. The pre-miRNA is then actively transported to the cytoplasm by Exportin-5 in a
RAS-related nuclear protein–guanosine triphosphate (GTP)-dependent manner and
further processed into a ~21-nucleotide duplex. The final step of miRNA maturation is
the selective loading of the functional strand of the small RNA duplex onto the RNA-
induced silencing complex (RISC). Mature miRNAs then guide the RNA-induced
silencing complex to cognate target genes and repress target gene expression by either
destabilizing target mRNAs or repressing their translation. DGRC8 (DiGeorge syndrome
critical region gene 8) and TRBP (TAR (HIV) RNA binding protein 2) are double-stranded
RNA-binding proteins that facilitate mature miRNA biogenesis by Drosha and Dicer
RNase III emzymes, respectively33,135–138.
122 | febRUARy 2008 | volUMe 8
© 2008 Nature Publishing Group
A technique for measuring the
transcription of genes. It
involves hybridization of
fluorescently labelled cDNA
prepared from a cell or tissue
of interest with glass slides or
other surfaces dotted with
thousands of oligonucleotides
or cDNA, ideally representing
all expressed genes in the
Polysomes (or polyribosomes)
are a cluster of ribosomes that
are attached along the length
of a single molecule of mRNA.
Polysomes read this mRNA
simultaneously, helping to
synthesize the same protein at
different spots on the mRNA. A
polysome profile refers to the
distribution of polysomes as
determined by gradient
centrifugation of cytoplasmic
extracts. The method is used to
study the association of
mRNAs with ribosomes.
The 7-methylguanosine that is
linked by a triphosphate bridge
to the first transcribed
nucleotide at the 5′ end of
eukaryotic mRNA. Recognition
of the m7G cap by the cap-
binding protein eIF4E is the
initiation step of cap-
Argonaute (AGO) proteins
A large family of ~95 KDa
proteins that contain conserved
PAZ (piwi, argonaut and zwille)
and PIWI domains and are
involved in post-transcriptional
gene silencing. Mammals have
four AGO family members
(AGO1, AGO2, AGO3 and
AGO4), each of which might be
a component of an RNA-
induced silencing complex.
This term refers to the seven
nucleotides found at the 5′
region of an miRNA
(nucleotides 2–8). Many
prediciton programmes require
an exact Watson–Crick
between the target sites and
the seed nucleotides of a
suggest that miRNAs may inhibit ribosome movement
along mRNAs, indicating that translational repression by
miRNAs might be due to the inhibition of translation ini-
tiation or the inhibition of elongation or the enhancement
of ribosomal drop-off from translating polysomes.
Mounting evidence suggests that miRNAs may inhibit
target gene expression by blocking translation initiation.
Pillai et al. showed that target gene repression by let-7a
miRNA occurs at the initiation stage of mRNA transla-
tion possibly by interfering with the recognition of the
m7G cap by the cap-binding protein60. Similarly, miRNAs
were shown to inhibit the initiation of target mRNA
translation in in vitro cell-free translational repression
assays61–63. Supporting this possibility, Kiriakidou et al.
have identified a cap-binding-protein-like motif in
human argonaute 2 (AGo2) proteins that is essential
for miRNA-mediated target gene repression in human
cells; this suggests that AGo2 might inhibit translation
initiation by binding to the m7G cap on a target mRNA,
thereby impeding the binding of the cap-binding protein
eIf4e (eukaryotic translation initiation factor 4e)64.
These seemingly conflicting mechanisms of target
gene repression by miRNAs may on the one hand reflect
the different experimental systems used in various stud-
ies — that is, the types of miRNA, the reporters, the cell
lines or the cell lysates that were used. on the other
hand, these studies suggest the possibility of more than
one mechanism by which miRNAs can repress target
Regulatory targets of miRNA genes
It is evident that target-gene identification holds the key to
deciphering the molecular mechanisms by which miRNA
genes exert their biological functions in animals. Despite
the progress in computational target-gene prediction, find-
ing the functionally relevant targets of an miRNA remains
a difficult task. Many of the fundamental assumptions
and principles of miRNA and target-gene interactions
are derived from the early genetic studies carried out on
the lin-4 and lin-7 miRNAs and their interactions with
cognate target genes. based on these early analyses, it is
thought that miRNAs regulate the expression of target
genes by forming base-pair interactions with them, that
miRNAs generally form imperfect base pairs with target
sites located in the UTRs of their target mRNAs, that mul-
tiple miRNA binding sites in target UTRs are required for
efficient regulation, and that these sites are evolutionarily
conserved4–6,56. These principles provide the experimen-
tal foundation that has been used for the computational
identification of miRNA target genes.
Several groups have postulated that miRNA target
sites comprise a ‘core sequence’ that forms perfect or
near-perfect base pairs with seven or eight bases near the
5′ end of an miRNA (known as the seed nucleotides)65–68,
and independently developed computational algorithms
to predict miRNA target genes on the basis of this princi-
ple (reviewed in REF. 69). It is estimated that 30% to 92%
of human genes are regulated by miRNAs19,70. Recently,
computational programmes have been developed for
target-gene identification without recourse to have
revealed several general principles regarding miRNAs
and target-gene regulation: first, each miRNA can poten-
tially regulate a large number of protein-coding genes;
second, many miRNAs potentially act in combination
to regulate the same target gene(s); and third, predicted
miRNA target genes are not restricted to a particular
functional category or biological pathway, but rather
are involved in a wide variety of biological processes
(reviewed in REF. 69). The finding that a majority of pro-
tein-coding genes in D. melanogaster and mammals are
potentially regulated by miRNAs is astonishing19,70,72–75
and suggests that miRNA-mediated gene expression may
have a widespread influence on the protein composition
of animal cells2,53,76,77.
However, available miRNA target-gene prediction
algorithms are likely to have high false-positive and
false-negative rates. There is limited overlap between
the target genes that have been predicted by various
algorithms69, owing in part to our limited understand-
ing of the principles that govern miRNA-mediated
target-gene regulation. The general principles that
have been derived from the few genetically validated
miRNA targets are unlikely to be all-encompassing. In
fact, among the small group of genetically validated
target mRNAs there are clear exceptions to these
Target mRNAs are repressed as efficiently by
miRNA-binding sites in the 5′ UTR as by those in the
3′ UTR78, which suggests that miRNAs could repress
target genes through binding sites other than those
within the 3′ UTR. However, to date, computational
programmes have not been developed to search for
sites other than those within the 3′ UTRs. Moreover,
only a single, canonical miRNA target site is required
for the regulation of the cog‑1 and hairy mRNAs by the
lys-6 and mir-7 miRNAs, respectively, in C. elegans9,67,79.
Interestingly, perfect pairing of the seed nucleotides is
not required for cog‑1 regulation by the lys-6 miRNA80.
Moreover, the RNA secondary structure and RNA
sequences outside of the mature miRNA binding
regions have potent effects on target recognition81–83,
indicating a previously unappreciated complexity of
miRNA interactions with their target mRNAs. finally,
computational predictions can only suggest potential
physical interactions between miRNAs and mRNA tar-
gets, and thus many target genes predicted to date may
not be biologically relevant as specific miRNAs and
their predicted target genes may never be expressed in
the same cell.
miRNAs and lineage differentiation
As a fundamental layer of post-transcriptional gene
regulation, it is not surprising that miRNA genes have
diverse and crucial roles in mammals (reviewed in
REF. 3). by inactivating the essential protein compo-
nents of the miRNA and small interfering RNA (siRNA)
machinery, such as Dicer and AGo2, researchers
have revealed that this system has a crucial role in the
development of worms, flies, fish and mice (reviewed
in REF. 84). More importantly, the targeted deletions of
individual miRNA genes in mice have indicated their
essential role in the development and function of the
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Small interfering RNAs
(siRNAs). A class of double-
stranded RNAs (dsRNAs) of
~21 nucleotides in length,
generated from long dsRNAs.
siRNAs silence gene expression
by promoting the cleavage of
perfectly matched mRNAs.
siRNAs can also be generated
by in vitro synthesis and can be
used to ‘knockdown’ (that is, to
silence the expression of) a
(ChIP). The use of antibodies
specific for transcription factors
to precipitate nucleic-acid
sequences from chromatin for
cardiac and immune systems85–88. Altered expression lev-
els of miRNAs have been reported in various haemato-
poietic disorders, such as leukaemias and lymphomas.
In fact, distinct signatures of a group of miRNAs are
correlated with specific types of leukaemias89,90. The
importance of miRNA genes in haematopoiesis is fur-
ther supported by studies showing that dysregulation of
miRNA gene expression in haematopoietic-cell lineages
seems to contribute to cancer pathogenesis (reviewed
in REFS 91,92).
Using either miRNA cloning or microarray analyses,
researchers have identified groups of miRNAs that
are differentially or abundantly expressed by specific
haematopoietic tissues1,20,93–96. Neilson and colleagues
have characterized miRNA expression profiles in T cells
at various stages of their development by direct miRNA
cloning and sequencing. They have shown that in addi-
tion to changes in the levels of individual miRNAs
between distinct T-cell developmental stages, the global
miRNA levels vary dramatically in parallel with changes
in the translational capacity of the cell96. More interest-
ingly, miRNA profiling in naive, effector and memory
CD8+ T cells has revealed that a few highly expressed
miRNAs are dynamically regulated during antigen-
specific T-cell differentiation97. finally, genome-wide
chromatin immunoprecipitation (ChIP) analyses have
revealed that the expression of forkhead box P3 (foXP3),
a transcription factor that is required for the development
and function of regulatory T cells, may directly control
the expression of the miRNA miR-155, implicating
miR-155 in regulatory T-cell formation or function98.
These studies on the expression of miRNAs, which show
a dynamic expression pattern relative to the various
stages of development, set a solid foundation for further
examination of the role of miRNAs in T-cell development
in the thymus and peripheral lymphoid organs.
Many miRNAs that are also differentially regulated
in haematopoietic-cell lineages have important roles in
modulating the development and function of immune
cells and host–pathogen interactions (TABLE 1). one of the
first miRNAs that was shown to have a role in the devel-
opment of vertebrate immune cells was miR-181a; this
miRNA is highly expressed by cells in the thymus and
is expressed at lower levels by cells in the heart, lymph
nodes and bone marrow45,99,100. In the bone marrow,
miR-181a is expressed at higher levels by b220+ b cells
than by CD3+ T cells45. Specifically, miR-181a expression
in bone-marrow-derived b cells decreases during b-cell
maturation from the pro-b-cell to pre-b-cell stage of devel-
opment100. In addition, ectopic expression of miR-181a
in enriched haematopoietic stem and progenitor cells
(HSPCs) resulted in an increase in the percentage of
CD19+ b cells and a decrease in the percentage of CD8+
T cells in short-term mouse bone-marrow reconstitution
assays45, demonstrating that lineage-specific miRNAs
might have a role in regulating lymphocyte development.
Table 1 | RNAs that have an important role in the development and function of immune cells or in host–pathogen interactions
FunctionValidated immune targetsRefs
Limits PFV1 replication by targeting the viral genome
Required for T-cell differentiation, germinal centre B-cell responses and
responses to bacterial and viral infection
Regulates B-cell development and T-cell activation by targeting transcription
Regulates B-cell and T-cell development and modulates T-cell sensitivity to
antigens by controlling the expression of multiple phosphatases in the TCR
Response to bacterial infection as part of TLR–NF-κB signalling
Response to bacterial infection and involved in CREB signalling
Facilitates the replication of HCV through interactions at the 5′ UTR of the
PFV1 and ORF2
DUSP5, DUSP6, SHP2, PTPN22, BCL-2
IRAK1 and TRAF6114
miR-BART2An EBV-encoded miRNA that is up-regulated during the lytic stage, targeting
Accumulates at late stages of infection, targeting early viral mRNAs and
reduces susceptibility to CTLs
An HSV1-encoded miRNA that inhibits host-cell apoptosis through reducing
TGFβ and SMAD3 expression to maintain viral latency
An HCMV-encoded miRNA that interferes with NK-cell function by targeting
the host gene MICB.
BALF5, BamHI L fragment 5; BCL-2, B-cell lymphoma 2; CREB, cAMP-responsive-element-binding protein; CTL, cytotoxic T lymphocyte; DUSP, dual-specificity
protein phosphatase; EBV, Epstein–Barr virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HSV1, herpes simplex virus-1; IRAK, interleukin-1 receptor-
associated kinase; MICB, MHC-class-I-polypeptide-related sequence B; miRNA, microRNA; ND, not determined; NF-κB, nuclear factor-κB; NK, natural killer;
ORF2, open reading frame 2; PFV1, primate foamy virus type 1; PTPN22, protein tyrosine phosphatase, non-receptor type 22; SHP2, SH2-domain-containing
protein tyrosine phosphatase 2; SMAD3, mothers against decapentaplegic homologue 3; TCR, T-cell receptor; TGFβ, transforming growth factor-β; TLR, Toll-like
receptor; TRAF, TNF receptor-associated factor; UTR, untranslated region.
SV40 Viral large and small T antigens124
TGFβ and SMAD3
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© 2008 Nature Publishing Group
cells that are dominant in the
peritoneal and pleural cavities.
Their precursors develop in the
fetal liver and omentum, and in
adult mice, the size of the B-1-
cell population is kept constant
owing to the self-renewing
capacity of these cells.
B-1 cells recognize self
components, as well as
common bacterial antigens,
and they secrete antibodies
that tend to have low affinity
and broad specificity.
Interestingly, miR-181a, at least when considered alone
rather than in combination with other miRNAs, appears
to function as a lymphoid-lineage modulator rather than
as a developmental switch, as the increase in b-lineage cells
did not completely block the differentiation of lymphoid
and myeloid cell types. This may differ from the effects
exerted by lineage-specific transcription factors or onco-
genes, which, when ectopically expressed, can completely
shut down the differentiation of one cell lineage101.
Not surprisingly, other miRNAs with distinct expres-
sion profiles in haematopoietic or lymphoid cell types
were shown to have distinct roles in immune-cell
development. for example, miR-223, a myeloid-specific
miRNA, the expression of which might be controlled by
the myeloid-specific transcription factors PU.1 and mem-
bers of the C/ebP (CCAAT/enhancer-binding protein)
family, seems to have an important role in regulating
Recent studies also revealed that miR-150, an miRNA
that is specifically expressed by mature lymphocytes, has
a key role in b-cell differentiation93,100,104. In contrast to
miR-181a, the expression of miR-150 increases during
b-cell maturation in the bone marrow and T-cell matu-
ration in the thymus, but decreases rapidly when naive
T cells differentiate into T helper 1 (TH1) or TH2 cells93,100.
When ectopically expressed in HSPCs, miR-150 blocks
b-cell development at the transition from the pro-b-cell to
pre-b-cell developmental stage, leading to severe defects
in the production of mature b cells. Xiao and colleagues
further demonstrated the importance of miR-150 in
b-cell formation using gain- and loss-of-function mouse
models104. miR‑150-knockout mice have an approxi-
mately twofold increase in the number of splenic B-1 cells,
but have no apparent defect in the development of other
lymphoid-derived T- and b-cell types.
A slight delay in T-cell development was observed
in mice that express an miR-150 transgene early in life,
but, by 18 weeks of age, they had dramatically impaired
b-cell development with normal T-cell levels, which is
consistent with the phenotype observed by Zhou and col-
leagues100,104. According to target validation using a luci-
ferase reporter assay and the correlation between Myb and
miR-150 expression levels in wild-type mice compared
with miR-150-deficient mice, Myb might be a crucial
target of miR-150. Intriguingly, although it is known that
Myb has a key role in both b- and T-cell development,
overexpression or deletion of miR-150 in mice affects only
the development of b cells, but not T cells104. It is also of
interest that deletion of miR-150 in mice results in a sig-
nificant increase in the production of ‘natural’ antibodies
in the blood, and that miR-150 expression in b cells is
often rapidly downregulated following b-cell activation
with IgM-specific antibodies, CpG-containing DNA or
lipopolysaccharide104. These findings suggest that miR-150
has a role in regulating b-cell development but might also
have a role in adaptive or innate immune responses that is
yet to be fully explored. However, it is clear that miRNAs
are components of the molecular circuitry that controls
lymphocyte development, but that the characterization of
the role of miRNAs in the development of immune cells
is still in its infancy.
miRNAs and adaptive immune responses
In addition to regulating haematopoietic-cell lineage
differentiation, miRNAs also have an important role in
modulating adaptive immune responses in mice86,87,99.
The bic locus, a common retroviral integration site in
avian leukosis virus (Alv)-induced b-cell lymphomas,
encodes the bic non-coding RNA that may collaborate
with the oncogene Myc to control cell growth105. More
recently it was found that the bic non-coding RNA is
the primary transcript for miR-155 and therefore is now
referred to as bic/mir‑155 (REFS 106,107). This non-coding
RNA transcript and the mature miR-155 contained within
it are overexpressed in human b-cell lymphomas, includ-
ing diffuse large b-cell lymphomas, Hodgkin lymphomas,
and burkitt lymphomas107–109. Mice with a bic/mir‑155
transgene, the expression of which is targeted to b cells,
develop b-cell malignancy110.
Interestingly, mice deficient in the bic/mir‑155 gene
are viable and fertile but have profound defects in their
protective immune responses86,87. Mice carrying mutated
bic/mir‑155 alleles are less responsive to immuniza-
tions and are not protected from virulent Salmonella
typhimurium infection after immunization with a non-
virulent aroA mutant strain of the bacteria. Using both
gain-of-function and loss-of-function analyses, Thai et al.
elegantly demonstrated that miR-155 might control the
formation and response of germinal-centre b cells in
part by controlling cytokine production87. Consistent
with the role of miR-155 in b- and T-cell responses, the
expression of miR-155 is upregulated in b and T cells
following their activation, and the deletion of the
bic/mir‑155 gene in mice leads to pleiotropic defects
in the function of b cells, T cells and dendritic cells86.
Significantly, in these miR-155-deficient mice, less IgM-
switched antigen-specific antibodies are produced by
activated b cells compared with control cells and the weak
production of interleukin-2 (Il-2), Il-4 and interferon-γ
(IfNγ) by activated T cells that is observed in response to
immunization indicates impaired b- and T-cell-mediated
immune responses, possibly due to a biased differentia-
tion toward TH2 cells compared with TH1 cells86,87. These
studies establish a crucial role for miR-155 in the adap-
tive immune response. further characterization of the
function of miR-155 function in various immune cell
populations and the identification of functionally rel-
evant target genes will help elucidate the molecular and
cellular mechanisms by which miR-155 regulates b- and
T-cell responses and protective immunity.
In another study, li et al. demonstrated that
miR-181a can function to modulate the strength and
threshold of T-cell receptor (TCR) signalling, thereby
influencing T-cell sensitivity to antigens99 (FIG. 3). In this
sense miR-181a acts like a rheostat, or dimmer switch,
in that it modulates cell pathways rather than simply
turning them on or off. ectopic miR-181a expression
in mature T cells augments their sensitivity to peptide
antigens, whereas inhibition of miR-181a in immature
T cells reduces sensitivity and impairs both positive and
negative selection. Moreover, the quantitative regulation
of TCR signalling strength by miR-181a can lead to a
change in the TCR signalling threshold and can enable
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Nature Reviews | Immunology
Reduced or inhibited proliferation
and cytokine production
and cytokine production
a Low miR-181a expression in mature effector T cells
b High miR-181a expression in immature T cells
Phosphatases or other
negative regulators of
Phosphatases or other
negative regulators of
mature T cells to recognize antagonists as agonists, dem-
onstrating the intricate relationship between quantitative
regulation and the switch-like response in immune cells.
More importantly, miR-181a controls the TCR signalling
threshold and strength in part by simultaneously damp-
ening the expression of multiple phosphatases that are
negative regulators of distinct steps of the TCR signalling
cascade, such as SHP2 (SH2 (SRC homology 2)-domain-
containing protein tyrosine phosphatase 2), PTPN22
(protein tyrosine phosphatase, non-receptor type 22),
DUSP5 (dual-specificity protein phosphatase 5) and
DUSP6. Multi-target regulation by miR-181a is required
for fine-tuning T-cell sensitivity, as knocking down
individual phosphatases by specific short-hairpin RNAs
(shRNAs) cannot recapitulate the effects of miR-181a
overexpression, whereas restoring the expression of
single phosphatases does reduce and/or abrogate the
effects of miR-181a overexpression. These findings
reveal that the T-cell threshold and sensitivity to antigens
is controlled by a network of genes at distinct stages of
TCR signalling, and provide solid evidence as to how
multi-target regulation by miRNA genes is used to carry
out such a task.
In addition, the dynamic regulation of miR-181a
expression during T-cell development and maturation
seems to correlate with changes in T-cell sensitivity
to antigens99,111. Inhibition of miR-181a expression in
immature T cells reduces antigen sensitivity and impairs
both positive and negative selection. The sensitivity of
T cells to antigen is intrinsically regulated to ensure the
proper development of T-cell specificity and sensitivity
to foreign antigens while avoiding self recognition.
In immature CD4+CD8+ double-positive thymocytes,
low-affinity antigenic peptides that are unable to activate
mature effector T cells are sufficient to induce strong
activation and clonal deletion112, whereas antagonists
that are normally inhibitory to effector T cells can
induce positive selection113. However, little is known
about the intrinsic molecular programmes that control
this. Therefore, miR-181a might in part contribute to the
fine tuning and intrinsic regulation of T-cell sensitivity
to antigens, thus, having a central role in the develop-
ment and maintenance of tolerance and immunity.
of note, miR-181a, which is dynamically regulated
during T-cell and b-cell maturation, may also have an
important role in other immune cell types96,99,100. As
many of the phosphatase targets regulated by miR-181a
are also expressed in distinct T- and b-cell subsets, one
intriguing possibility is that miR-181a could modulate
different receptor signalling pathways by controlling the
expression of similar target phosphatase genes (FIG. 3).
Indeed, we have found that miR-181a promotes early
T-cell development in the thymus through potentiating
pre-TCR and Notch signalling (T. K. Mao and C.-Z.C.,
unpublished observations). However, miR-181a is likely
to have other roles in T-cell function. The ectopic expres-
sion of miR-181a influences the co-stimulatory pathway
through presently unknown targets99. miR-181a may also
regulate the expression of anti-apoptotic proteins, such
as b-cell lymphoma 2 (bCl-2) and the cell surface regu-
lator CD69 (REF. 96). These findings suggest that further
characterization of the molecular networks controlled
by miR-181a would probably yield additional insights
about other possible functions for miR-181a in adaptive
miRNAs and innate immune responses
miRNAs may also have crucial roles in regulating the
innate immune response, the first line of defence that relies
on phagocytes, such as granulocytes and macrophages.
TlRs have a major role in the recognition of invading bac-
teria, viruses and other pathogens, and in the initiation of
the innate immune response. Triggered by ligand binding,
TlR-mediated signalling starts with the recruitment of
adaptor proteins to the receptor, followed by stimulation
Figure 3 | Modulation of the antigen sensitivity of T cells by the miR‑181a dimmer
switch (or rheostat). a | In mature effector T cells, microRNA-181a (miR-181a) is
expressed at low levels and therefore the signalling rheostat is tuned to high resistance.
That is, by decreasing miR-181a expression and de-repressing the negative signals that
are controlled by the negative regulators of T-cell receptor (TCR) signalling (such as SH2
(SRC homology 2)-domain-containing protein tyrosine phosphatase 2 (SHP2), protein
tyrosine phosphatase, non-receptor type 22 (PTPN22), dual-specificity protein
phosphatase 5 (DUSP5) and DUSP6) the signal output, such as T-cell proliferation and
cytokine secretion induced by peptide–MHC complexes, is dramatically reduced or
completely turned off. b | By contrast, in immature T cells, such as double-positive
thymocytes, miR-181a is expressed at high levels and thus the rheostat is tuned to low
resistance. That is, by increasing miRNA expression and repressing the negative signals
that are controlled by the negative regulators of TCR signalling, the signal output from the
identical stimulation is dramatically enhanced. The expression of miR-181a is regulated
during T-cell development and maturation, and the level of miR-181a expression
correlates with T-cell sensitivity to antigens, suggesting that miR-181a might act as an
intrinsic rheostat or dimmer switch to tune T-cell sensitivity to antigens during T-cell
development and maturation. Other miRNA ‘rheostats’ might be used in different cell
types and for different receptors when the miRNA and corresponding targets coexist.
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Nature Reviews | Immunology
of a protein kinase cascade that consequently activates
transcription factors, such as activator protein 1 (AP1)
and nuclear factor-κb (Nf-κb), and ultimately resulting
in immune gene expression.
Recently, three miRNAs, miR-146a, miR-132 and
miR-155, were found to be regulated in response to
immune-cell stimulation by endotoxins114. When mono-
cytes were treated with the endotoxin lipopolysaccharide
(lPS) to mimic signalling by a bacterial infection, the
expression levels of these three miRNAs were dramati-
cally increased. Interestingly, induction of miR-146a
expression can only be triggered by the TlRs that reside
on the cell surface and recognize bacterial constituents,
but not by the intracellular TlRs that mainly sense viral
nucleic acids, suggesting that miR-146a may respond to
bacterial invasion rather than viral infection. In addition,
the inducible expression of miR-155, an miRNA that (as
discussed before) is important for b-cell function and
is associated with b-cell developmental disorders, was
observed in both bacterial and viral infection events as
a result of TlR3-induced tumour-necrosis factor (TNf)
autocrine signalling114,115. These findings clearly indicate
that miRNAs may be integral components of innate
immune responses, and that further characterization of
the role of miRNAs will probably reveal novel insights
into the molecular mechanisms by which miRNAs regu-
late innate immune responses.
emerging evidence also suggests that miRNA-
mediated gene regulation may serve as a defence mecha-
nism against viral infections in vertebrate cells, thereby
providing another layer to the innate immune response.
Certain host miRNAs appear to have evolved to regu-
late viral infection. Human miR-32 contributes to the
repression of the replication of the retrovirus primate
foamy virus type 1 (Pfv1) in cultured human cells by
binding to partially complementary sites in the 3′ UTRs
of five different Pfv1-derived mRNAs116. The down-
regulation of these five viral target genes by miR-32
slows Pfv1 replication. This study identified a human
cellular miRNA that has an antiviral function, and sug-
gests a possibly broad impact of miRNA-mediated gene
regulation on viral infection. further supporting this
idea, Pedersen et al. have recently shown that the IfN-
signalling system, the key defence mechanism against
viral infection in mammalian cells, works in concert
with miRNAs to control viral infection117. They have
shown that IfNβ can induce the expression of numerous
cellular miRNAs. Specifically, eight of the IfNβ-induced
miRNAs (miR-1, miR-30, miR-128, miR-196, miR-296,
miR-351, miR-431 and miR-448) have seed nucleotides
that form near-perfect base pair matches with the HCv
genome and may contribute to the antiviral effects of
IfNβ against HCv. Interestingly, IfNβ also induces the
downregulation of the expression of miR-122, an miRNA
that has been shown to be essential for HCv replication
in liver cells118. These findings provide clear evidence
that cellular miRNAs are integrated components of
the mammalian innate immune response, and present
another dimension to innate immunity that is based
on direct interactions between viral and host-encoded
Not surprisingly, such a gene regulatory mecha-
nism may also be exploited by viruses to facilitate their
infection (FIG. 4)119–121. Many viruses have been found
to encode miRNAs that regulate both viral and host
mRNAs (reviewed in REF. 121). viruses that encode
such miRNAs include the epstein–barr virus (ebv),
Kaposi’s sarcoma-associated herpes virus (KSHv)
and cytomegalovirus (CMv)122–125. In cells latently
infected with ebv, different miRNAs are expressed
during different stages, suggesting that viral miRNAs
contribute to the regulation and maintenance of viral
latency122,123. miR-lAT is an miRNA encoded by herpes
simplex virus-1 (HSv1) that maintains host cell latency
and inhibits cell apoptosis by reducing transforming
growth factor-β (TGfβ) and SMAD3 (mothers against
decapentaplegic homologue 3) expression in the
host cell, thereby interfering with TGfβ-dependent
signalling and preventing host cell death126. finally, a
human cytomegalovirus (HCMv)-encoded miRNA,
miR-Ul112, represses the expression of MHC-class-I-
polypeptide-related sequence b (MICb). MICb is a
stress-induced ligand of the natural-killer cell (NK
cell)-activating receptor NKG2D (natural-killer
group 2, member D), which is required for NK-cell-
mediated killing of virus-infected cells127. These results
demonstrate that HCMv evades immune surveillance
by targeting a cellular mRNA with a virally encoded
miRNA, and suggest that viruses use miRNAs not only
to regulate their own life cycles but also to evade host
Figure 4 | MicroRNAs in host–pathogen interaction. Host microRNAs (miRNAs) may
interfere with viral infections by interacting with viral genomes. In human cells, after
infection of the retrovirus primate foamy virus type 1 (PFV1), host cell miR-32 binds to
partial complementary sites in the viral 3′ untranslated region (UTR) that is shared by
five PFV1 mRNAs, leading to reduced viral replication. To repress host miRNA
machinery, PFV1 produces Tas, a virus-encoded RNA interference suppressor protein
that inhibits host miRNA function by targeting RNA-interfering silencing complex
(RISC), to counteract the host antiviral response. By contrast, hepatitis C virus (HCV)
can exploit miRNA-mediated gene regulation to facilitate its replication by recruiting
a liver-cell specific miRNA, miR-122, to bind the viral RNA at the 5′ UTR. DGRC8,
DiGeorge syndrome critical region gene 8; GTP, guanosine triphosphate; TRBP, TAR
(HIV) RNA binding protein 2.
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A mechanism for RNA-guided
regulation of gene silencing in
which double-stranded RNA
inhibits the expression of genes
In an interesting twist, albeit with an opposite
outcome, miR-122, which is highly abundant and spe-
cifically expressed by liver cells, actually facilitates the
replication of the hepatitis C virus (HCv) through inter-
actions at the 5′ UTR of the HCv RNA118. These results
demonstrate that HCv has evolved to exploit miRNA-
mediated gene regulation to facilitate its replication
through an as yet unknown mechanism. As noted above,
animal miRNAs have so far only been shown to act at the
post-transcriptional level to repress gene expression.
It is interesting to note that most viral miRNAs
identified so far have no substantial homology to one
another or to any known animal miRNAs. Moreover,
miRNAs are only found in DNA viruses and not in RNA
viruses or retroviruses123. It is also intriguing that no
viral-encoded siRNAs have been identified in virus-
infected cells122,123. In addition to encoding miRNAs
that regulate their own genes and host genes, certain
viruses encode silencing suppressor proteins that
counteract miRNA or siRNA-mediated immunity. It is
thought that Pfv1 has such a mechanism to suppress
miR-32 function to allow it to successfully infect cells.
Indeed Pfv1 encodes the silencing suppressor Tas that
can interfere with the miR-32-mediated downregulation
of its mRNA in a nonspecific manner116. Similarly,
HIv-1 uses Tat, one of its transcriptional activators,
as an miRNA-silencing suppressor that interferes with
Dicer function and prevents the processing of double-
stranded RNA (dsRNA) into siRNA128,129. Interestingly,
a Tat-deficient HIv-1 strain does not spread effectively
in human cells, perhaps due in part to its inability to
suppress RNA interference in the host cell, although this
hypothesis needs to be further investigated. These studies
depict yet another defensive factor that viruses use to
evade host miRNA-based immunity and optimize their
ability to infect and replicate. Collectively, the discovery
that both viruses and hosts use miRNAs for their own
advantages introduces a new level of gene regulation
that modulates pathogen–host interactions.
These studies provide initial evidence that many
haematopoietic-cell-specific or lineage-specific miRNAs
have a key role in regulating the development of differ-
ent types of immune cells. However, much remains to
be learned before we will be able to integrate the post-
transcriptional genetic programmes that are controlled
by miRNA genes into the genetic circuitry that main-
tains the homeostasis of the immune system. Many
growth factors and transcription factors have key roles in
regulating cell-lineage determination, cell proliferation
and differentiation, and selection checkpoints during
lymphopoiesis130,131. However, the quantitative regulation,
which determines the size of the stem-cell or progenitor-
cell pools, cell-cycle progression, the rate of cell division,
and the kinetics and timing and/or order of lineage
differentiation, remains largely unknown. Such dynamic
and finely tuned processes are likely to be regulated by
quantitative gene regulatory mechanisms.
Compared with other gene regulatory mechanisms,
such as chromatin modification and transcriptional
controls, miRNA-mediated gene regulation occurs at
the step directly before protein synthesis, and thus may
be more suited for the fine-tuning of gene expression and
quantitative regulation2. More generally, miRNAs provide
a mechanism for managing gene expression, allowing
mRNAs to be translated at one stage of differentiation and
then shut off at a slightly later stage. It has been proposed
that, at the molecular level, certain miRNA genes func-
tion as rheostats by precisely regulating the quantitative
levels of protein synthesis and thus many other biological
processes. The degree of gene repression achieved by an
miRNA may be quantitatively dependent on the number
of target sites on the target UTR, the degree of pairing to
the miRNA, the levels of miRNA expressed, the presence
of other miRNAs that regulate the same target gene and
the cleavage of the target RNAs2.
furthermore, these early studies clearly demonstrate
that miRNAs have a central role in modulating immune
responses. As a fundamental type of genetic programme,
it is likely that miRNA-mediated post-transcriptional
gene expression has important roles in many aspects of
adaptive and innate immune responses. Discovering the
biological functions of miRNA genes and the molecular
networks controlled by these non-coding RNA genes
would probably fill some of the gaps in our existing
knowledge and possibly reveal novel concepts about the
regulation of the immune system. Given the crucial role
that miRNA genes could have in modulating immune
responses, it is likely that any dysregulation of miRNA
expression may contribute to the pathogenesis of certain
The complete impact of miRNAs on the immune sys-
tem has yet to be fully understood and many interesting
questions remain to be answered before we can unravel
all of the functions of miRNAs and integrate miRNA-
mediated gene regulation with other cellular genetic
regulatory networks. further characterization of miRNA-
mediated gene regulation during haematopoiesis should
shed light on the homeostatic control of haematopoietic
stem-cell self-renewal and lineage differentiation, and also
provide insights as to how aberrant miRNA regulation may
contribute to autoimmune diseases, leukaemias and other
blood-related pathological disorders. finally, one could
envision in the future the development of novel therapeutics
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We thank members of the Chen and Lodish laboratories
and also V. Ambros for his helpful comments on this manu-
script. This research on miRNAs is supported by grants
1R01HL081612-01 to C.-Z. C. and 5R01DK068348 to H.F.L.
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
DUSP5 | DUSP6 | miR-146a | miR-150 | miR-155 | miR-181a |
PTPN22 | SHP2
miRBase targets: http://microrna.sanger.ac.uk/targets/v4/
miRNA registry: http://microrna.sanger.ac.uk/sequences/
All liNks ARe AcTiVe iN The oNliNe pdF
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