The Protean Nature of Cells
in the B Lymphocyte Lineage
Richard R. Hardy,1,* Paul W. Kincade,2and Kenneth Dorshkind3
1The Division of Basic Sciences, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
2The Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
3The Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
The subdivision of bone marrow (BM) with surface markers and reporter systems and the use of mul-
tiple culture and transplantation assays to assess differentiation potential have led to extraordinary
progress in defining stages of B lymphopoiesis between the hematopoietic stem cell and B cell
receptor (BCR)-expressing lymphocytes. Despite the lack of standard nomenclature and a series
of technical issues that still need to be resolved, there seems to be a general consensus regarding
tean and able to alter their differentiation potential during embryogenesis and after birth in response
to infections suggests that a full understanding of B cell development and how it is regulated has not
yet been attained.
The Early Events
Hematopoietic stem cells (HSCs), defined by their exten-
sive self-renewal capacity and potential to generate all
blood-cell lineages, become restricted to the B lympho-
cyte lineage through progressive stages of differentiation
that have been characterized by several groups. HSCs
are identified by expression of high amounts of the recep-
tor for stem cell factor, c-kit (CD117), and the absence
of cell-surface proteins expressed on differentiated mye-
loid, erythroid, and T lineage cells. This lineage-negative
(Lin–), CD117hifraction of BM cells is highly enriched for
long-term repopulating HSCs (Spangrude et al., 1988).
Recently, expression of the CD150 member of the SLAM
family of molecules has been shown to greatly enrich for
HSCs within this CD117hiLin–fraction (Kiel et al., 2005).
Other correlates to transition from HSCs to short-term
repopulating stem cells and primitive progenitors include
loss of the adhesion molecule VCAM-1 and CD90 (Thy-1)
along with acquisition of the growth-factor receptor Flk-2
(Flt-3) and CD27.
Correlating changes in cell lineage potential, assayed
in vitro or in vivo, with cell-surface phenotype has been
a powerful tool used to resolve the earliest stages of B
cell development from HSCs (Figure 1). Primitive cells,
termed ‘‘early lymphoid progenitors’’ (ELPs), within the
CD117hiLin–fraction that exhibit lymphoid or B lineage
bias have been described based on their expression of
genes considered lymphocyte restricted. Thus, transcrip-
tion of terminal deoxynucleotidyl transferase (TdT), a gene
that mediates nontemplated nucleotide additions during
antigen receptor recombination, initiates very early. Acti-
vation of the lymphocyte-restricted recombinase activat-
ing genes, particularly Rag-1, initiates in a fraction of the
TdT+ELPs, and such cells appear particularly lymphoid
biased (Igarashi et al., 2002). High sensitivity to steroid
hormones also helps to distinguish early, lymphoid-spec-
ified progenitors from cells dedicated to other lineages
(Medina et al., 2001). Much more needs to be learned
on timely expression of the Ikaros, PU.1, E2A, and EBF1
transcription factors (Busslinger, 2004).
ELPsdonot expressthe receptorfor IL-7,CD127,butin
the BM they progress to generate CD127+common lym-
phoid progenitors (CLPs). CLPs were originally described
asbeing lymphoid-committed cellsthathadlostthe ability
to generate most other hematopoietic lineages (Kondo
et al., 1997). Textbook models of hematopoietic develop-
ment view them as a branch-point between the B and T
lineages, but more recent work has suggested that the
thymus is likely seeded by more primitive progenitors (All-
man et al., 2003). Furthermore, the presence of extensive
Ig heavy-chain DJ rearrangements in CLPs (Rumfelt et al.,
2006) and their rapid progression to early stages of B lin-
eage development suggest that most are early B cell pro-
genitors that retain residual potential for generation of
alternate lineages. In addition to B cells, CLPs as originally
defined by Kondo and colleagues (Lin–Sca1+CD117+
CD127+) also represent major intermediates en route to
becoming NK cells (Hirose et al., 2002; Kondo et al.,
1997; Welner et al., 2007).
Lineage Stability Is Acquired Gradually
Lineage potential of precursors can be tested in vivo by
cell transfer or in vitro by a diverse array of assays. The
most widely used in vivo assay for assessing hematopoi-
etic lineage potential is competitive repopulation of le-
thally irradiated mice with donor cells from Ly5 disparate
congenic animals (Uchida et al., 1994). An advantage of
this approach is that differentiation potentially occurs in
Immunity 26, June 2007 ª2007 Elsevier Inc.
a physiologic environment, with the caveats that irradia-
tion may alter cell homing patterns and substantially per-
turb delicate microenvironmental niches. This approach
has established the broad outlines of progressive restric-
tion to distinct hematopoietic lineages, including the CLP
and common myeloid progenitor (CMP) stages (Terskikh
et al., 2003).
The oldest procedure for determining the capacity of
progenitors to generate diverse hematopoietic cell fates
This procedure, together with fetal thymic organ culture
and long-term BM culture (‘‘stromal cell culture’’), are the
classic approaches for differentiation of all blood-cell line-
ages. An interesting recent development has been the
application of a Delta1-transduced stromal cell line that
permits generation of T lineage cells without the complex
procedure of fetal organ culture (Schmitt and Zuniga-
Pflucker, 2002) and that can be readily applied in single-
cell analysis (Rumfelt et al., 2006). Various single-cell
procedures have been developed that enable the lineage
potential of smaller numbers of highly purified progenitors
to be analyzed.
Traditional modelsofhematopoiesis depictitasarather
However, the use of increasingly sophisticated in vitro
assays has revealed that lineage biases, read out in vivo
as absolute, may not actually be so. For example, analysis
of CLP-stage cells that appear lymphoid restricted when
assayed in vivo reveals some degree of myeloid potential
in single-cell stromal-cell culture (Balciunaite et al., 2005;
Rumfelt et al., 2006). This view has been corroborated
by use of fluorescent reporters that assess activation of
and development. In this regard, genes such as Rag1 and
Rag2 are first expressed in cells of the ELP (Igarashi et al.,
2002) and multilineage progenitor (MLP) (Rumfelt et al.,
2006) stages that retain substantial myeloid potential. In
parison of data on lineage restriction of variously delin-
eated precursor populations by in vivo and in vitro assays
reveals a more stochastic picture in which lymphoid spec-
ification occurs as a gradual rather than abrupt process.
Thus, cells at early stages exhibit a lymphoid ‘‘bias’’ rather
than ‘‘commitment’’ in that they are efficient in generating
Figure 1. A Framework for Delineating Progressive Stages in Development of B Lineage Cells in Mouse Bone Marrow, Based
on Ordered Changes in Cell-Surface Molecules
Cell-surface expression shown in the beige box. Gene expression assessed by analysis of mRNA, reporter constructs, or cytoplasmic staining is
shown in the violet box. Note that the ELP cell fraction, identified by cytoplasmic expression of Tdt or a Rag1 GFP reporter, is contained within
the MLP subset,identified by cell-surface analysis. Abbreviations: HSC, hematopoietic stem cells; MLP,multilineage progenitor; ELP, early lymphoid
progenitor; NF B, newly formed B cell; Fo B, follicular B cell.
Immunity 26, June 2007 ª2007 Elsevier Inc.
Kluiver, J., Kroesen, B.J., Poppema, S., and van den Berg, A. (2006).
The role of microRNAs in normal hematopoiesis and hematopoietic
malignancies. Leukemia 20, 1931–1936.
Kondo, M., Weissman, I.L., and Akashi, K. (1997). Identification of clo-
nogenic common lymphoid progenitors in mouse bone marrow. Cell
Kondo, K., Scherer, D.C., Miyamoto, T., King, A.G., Akashi, K., Suga-
mura, K., and Weissman, I.L. (2000). Cell-fate conversion of lymphoid-
committed progenitors by instructive actions of cytokines. Nature 407,
Krueger, A., and von Boehmer, H. (2007). Identification of a T lineage-
committed progenitor in adult blood. Immunity 26, 105–116.
Lacaud, G., Carlsson, L., and Keller, G. (1998). Identification of a fetal
hematopoietic precursor with B cell, T cell, and macrophage potential.
Immunity 9, 827–838.
Laiosa, C.V., Stadtfeld, M., and Graf, T. (2006). Determinants of lym-
Lalor, P.A. (1991). An evolutionarily-conserved role for murine Ly-1 B
Lam, K.P., and Rajewsky, K. (1998). Rapid elimination of mature autor-
eactive B cells demonstrated by Cre-induced change in B cell antigen
receptor specificity in vivo. Proc. Natl. Acad. Sci. USA 95, 13171–
Lam, K.P., and Rajewsky, K. (1999). B cell antigen receptor specificity
and surface density together determine B-1 versus B-2 cell develop-
ment. J. Exp. Med. 190, 471–477.
Li, Y.S., Hayakawa, K., and Hardy, R.R. (1993). The regulated expres-
sion of B lineage associated genes during B cell differentiation in bone
marrow and fetal liver. J. Exp. Med. 178, 951–960.
Li, Y.S., Wasserman, R., Hayakawa, K., and Hardy, R.R. (1996). Iden-
tification of the earliest B lineage stage in mouse bone marrow. Immu-
nity 5, 527–535.
Luqman, M., Johnson, P., Trowbridge, I., and Bottomly, K. (1991). Dif-
ferential expression of the alternatively spliced exons of murine CD45
in Th1 and Th2 cell clones. Eur. J. Immunol. 21, 17–22.
Mandik-Nayak, L., Seo, S.J., Sokol, C., Potts, K.M., Bui, A., and Erik-
son, J. (1999). MRL-lpr/lpr mice exhibit a defect in maintaining devel-
opmental arrest and follicular exclusion of anti-double-stranded DNA
B cells. J. Exp. Med. 189, 1799–1814.
Marshall, A.J., Doyen, N., Bentolila, L.A., Paige, C.J., and Wu, G.E.
(1998). Terminal deoxynucleotidyl transferase expression during neo-
natal life alters D(H) reading frame usage and Ig-receptor-dependent
selection of V regions. J. Immunol. 161, 6657–6663.
immune repertoire. Marginal zone and B1 B cells as part of a ‘‘natural
immune memory’’. Immunol. Rev. 175, 70–79.
Martin, F.,Oliver,A.M.,andKearney,J.F.(2001). MarginalzoneandB1
B cells unite in the early response against T-independent blood-borne
particulate antigens. Immunity 14, 617–629.
Martin, C.H., Aifantis, I., Scimone, M.L., von Andrian, U.H., Reizis, B.,
von Boehmer, H., and Gounari, F. (2003). Efficient thymic immigration
of B220+ lymphoid-restricted bone marrow cells with T precursor po-
tential. Nat. Immunol. 4, 866–873.
Masmoudi, H., Mota-Santos, T., Huetz, F., Coutinho, A., and Caze-
nave, P.A. (1990). All T15 Id-positive antibodies (but not the majority
of VHT15+ antibodies) are produced by peritoneal CD5+B lympho-
cytes. Int. Immunol. 2, 515–520.
Medina, K.L., Garrett, K.P., Thompson, L.F., Rossi, M.I., Payne, K.J.,
and Kincade, P.W. (2001). Identification of very early lymphoid precur-
sors in bone marrrow and their regulation by estrogen. Nat. Immunol.
Medina, K.L., Pongubala, J.M., Reddy, K.L., Lancki, D.W., Dekoter, R.,
Kieslinger, M., Grosschedl, R., and Singh, H. (2004). Assembling a gene
Meresse, B., Curran, S.A., Ciszewski, C., Orbelyan, G., Setty, M.,
Bhagat, G., Lee, L., Tretiakova, M., Semrad, C., Kistner, E., et al.
(2006). Reprogramming of CTLs into natural killer-like cells in celiac
disease. J. Exp. Med. 203, 1343–1355.
Merrell, K.T., Benschop, R.J., Gauld, S.B., Aviszus, K., Decote-Ri-
cardo, D., Wysocki, L.J., and Cambier, J.C. (2006). Identification of
anergic B cells within a wild-type repertoire. Immunity 25, 953–962.
Mikkola, I., Heavey, B., Horcher, M., and Busslinger, M. (2004). Rever-
sion of B cell commitment upon loss of Pax5 expression. Science 297,
Montecino-Rodriguez, E.,and Dorshkind,K.(2002). Identification of B/
macrophage progenitors in adult bone marrow. Semin. Immunol. 14,
Montecino-Rodriguez, E., Leathers, H., and Dorshkind, K. (2006).
Identification of a B-1 B cell-specified progenitor. Nat. Immunol. 7,
Monticelli, S., Ansel, K.M., Xiao, C., Socci, N.D., Krichevsky, A.M.,
Thai, T.H., Rajewsky, N., Marks, D.S., Sander, C., Rajewsky, K.,
et al. (2005). MicroRNA profiling of the murine hematopoietic system.
Genome Biol. 6, R71.
Muller, A.M., Medvinsky, A., Strouboulis, J., Grosveld, F., and Dzier-
zak, E. (1994). Development of hematopoietic stem cell activity in the
mouse embryo. Immunity 1, 291–301.
Nagai, Y., Garrett, K.P., Ohta, S., Bahrun, U., Kouro, T., Akira, S.,
Takatsu, K., and Kincade, P.W. (2006). Toll-like receptors on hemato-
poietic progenitor cells stimulate innate immune system replenish-
ment. Immunity 24, 801–812.
Nagaoka, H., Gonzalez-Asequinolaza, G., Tsuji, M., and Nussenzweig,
M.C. (2000). Immunization and infection change the number of recom-
bination activating gene (RAG)-expressing B cells in the periphery by
altering immature lymphocyte production. J. Exp. Med. 191, 2113–
Nagasawa, T. (2006). Microenvironmental niches in the bone marrow
required for B-cell development. Nat. Rev. Immunol. 6, 107–116.
Nemazee, D.A., and Burki, K. (1989). Clonal deletion of B lymphocytes
in a transgenic mouse bearing anti-MHC class I antibody genes.
Nature 337, 562–566.
Nutt, S.L., and Kee, B.L. (2007). The transcriptional regulation of B cell
lineage commitment. Immunity 26, this issue, 715–725.
Nutt, S.L., Heavey, B., Rolink, A.G., and Busslinger, M. (1999). Com-
mitment to the B-lymphoid lineage depends on the transcription factor
Pax5. Nature 401, 556–562.
translation from mice to humans. Immunity 26, this issue, 674–
Perry, S.S., Welner, R.S., Kouro, T., Kincade, P.W., and Sun, X.H.
(2006). Primitive lymphoid progenitors in bone marrow with T lineage
reconstituting potential. J. Immunol. 177, 2880–2887.
Petrenko, O., Beavis, A., Klaine, M., Kittappa, R., Godin, I., and
Lemischka, I.R. (1999). The molecular characterization of the fetal
stem cell marker AA4. Immunity 10, 691–700.
Petrie, H.T. (2007). Early commitment: T cell progenitors in the blood.
Immunity 26, 7–8.
Pillai, S., Cariappa, A., and Moran, S.T. (2004). Positive selection and
lineage commitment during peripheral B-lymphocyte development.
Immunol. Rev. 197, 206–218.
Roessler, S., Gyory, I., Imhof, S., Spivakov, M., Williams, R.R., Bus-
slinger, M., Fisher, A.G., and Grosschedl, R. (2007). Distinct promoters
mediate the regulation of Ebf1 gene expression by interleukin-7 and
Pax5. Mol. Cell. Biol. 27, 579–594.
Rolink, A., Grawunder, U., Winkler, T.H., Karasuyama, H., and Melch-
ers, F. (1994). IL-2 receptor alpha chain (CD25, TAC) expression de-
fines a crucial stage in pre-B cell development. Int. Immunol. 6,
Immunity 26, June 2007 ª2007 Elsevier Inc.
Rolink, A.G., Andersson, J., and Melchers, F. (1998). Characterization
of immature B cells by a novel monoclonal antibody, by turnover and
by mitogen reactivity. Eur. J. Immunol. 28, 3738–3748.
Rolink, A.G., Brocker, T., Bluethmann, H., Kosco-Vilbois, M.H., Ander-
sson, J., and Melchers, F. (1999). Mutations affecting either generation
or survival of cells influence the pool size of mature B cells. Immunity
Rolink, A.G., Andersson, J., and Melchers, F. (2004). Molecular mech-
anisms guiding late stages of B-cell development. Immunol. Rev. 197,
Rosenbauer, F., Owens, B.M., Yu, L., Tumang, J.R., Steidl, U., Kutok,
J.L., Clayton, L.K., Wagner, K., Scheller, M., Iwasaki, H., et al. (2006).
ulatory element of the gene encoding PU.1. Nat. Genet. 38, 27–37.
Rossi, M.I., Yokota, T., Medina, K.L., Garrett, K.P., Comp, P.C., Schi-
pul, A.H., Jr., and Kincade, P.W. (2003). B lymphopoiesis is active
throughout human life, but there are developmental age-related
changes. Blood 101, 576–584.
Rothenberg, E.V. (2007). Negotiation of the T lineage fate decision by
transcription-factor interplay and microenvironmental signals. Immu-
nity 26, this issue, 690–702.
Rumfelt, L.L., Zhou, Y., Rowley, B.M., Shinton, S.A., and Hardy, R.R.
(2006). Lineage specification and plasticity in CD19-early B cell pre-
cursors. J. Exp. Med. 203, 675–687.
Saito, T., Chiba, S., Ichikawa, M., Kunisato, A., Asai, T., Shimizu, K.,
Yamaguchi, T., Yamamoto, G., Seo, S., Kumano, K., et al. (2003).
Notch2 is preferentially expressed in mature B cells and indispensable
for marginal zone B lineage development. Immunity 18, 675–685.
Schiemann, B., Gommerman, J.L., Vora, K., Cachero, T.G., Shulga-
Morskaya, S., Dobles, M., Frew, E., and Scott, M.L. (2001). An essen-
tial role for BAFF in the normal development of B cells through
a BCMA-independent pathway. Science 293, 2111–2114.
Schmitt, T.M., and Zuniga-Pflucker, J.C. (2002). Induction of T cell de-
velopment from hematopoietic progenitor cells by delta-like-1 in vitro.
Immunity 17, 749–756.
Schneider, P., Takatsuka, H., Wilson, A., Mackay, F., Tardivel, A.,
Lens, S., Cachero, T.G., Finke, D., Beermann, F., and Tschopp, J.
(2001). Maturation of marginal zone and follicular B cells requires B
cell activating factorofthetumornecrosisfactor familyand isindepen-
dent of B cell maturation antigen. J. Exp. Med. 194, 1691–1697.
Sioud, M., Floisand, Y., Forfang, L., and Lund-Johansen, F. (2006).
Signaling through toll-like receptor 7/8 induces the differentiation of
J. Mol. Biol. 364, 945–954.
Sitnicka, E., Brakebusch, C., Martensson, I.L., Svensson, M., Agace,
W.W., Sigvardsson, M., Buza-Vidas, N., Bryder, D., Cilio, C.M., Ahle-
nius, H., et al. (2003). Complementary signaling through flt3 and inter-
leukin-7 receptor alpha is indispensable for fetal and adult B cell gen-
esis. J. Exp. Med. 198, 1495–1506.
Solvason, N., Lehuen, A., and Kearney, J.F. (1991). An embryonic
source of Ly1 but not conventional B cells. Int. Immunol. 3, 543–550.
Spangrude, G.J., Heimfeld, S., and Weissman, I.L. (1988). Purification
and characterization of mouse hematopoietic stem cells. Science 241,
Taieb, J., Chaput, N., Me ´nard, C., Apetoh, L., Ullrich, E., Bonmort, M.,
Pe ´guignot, M., Casares, N., Terme, M., Flament, C., et al. (2006). A
novel dendritic cell subset involved in tumor immunosurveillance.
Nat. Med. 12, 214–219.
Tanigaki,K., Han,H.,Yamamoto, N.,Tashiro, K.,Ikegawa, M.,Kuroda,
is involved in cell fate determination of marginal zone B cells. Nat. Im-
munol. 3, 443–450.
Terskikh, A.V., Miyamoto, T., Chang, C., Diatchenko, L., and Weiss-
man, I.L. (2003). Gene expression analysis of purified hematopoietic
stem cells and committed progenitors. Blood 102, 94–101.
Tiegs, S.L., Russell, D.M., and Nemazee, D. (1993). Receptor editing in
self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020.
Traver, D., Miyamoto, T., Christensen, J., Iwasaki-Arai, J., Akashi, K.,
and Weissman, I.L. (2001). Fetal livermyelopoiesis occurs through dis-
tinct, prospectively isolatable progenitor subsets. Blood 98, 627–635.
Tsan, M.F., and Gao, B. (2004). Endogenous ligands of Toll-like recep-
tors. J. Leukoc. Biol. 76, 514–519.
Tudor, K.S., Payne, K.J., Yamashita, Y., and Kincade, P.W. (2000).
Functional assessment of precursors from murine bone marrow sug-
gets a sequence of early B-lineage differentiation events. Immunity
Tung, J.W., Mrazek, M.D., Yang, Y., Herzenberg, L.A., and Herzen-
berg, L.A. (2006). Phenotypically distinct B cell development pathways
map to the three B cell lineages in the mouse. Proc. Natl. Acad. Sci.
USA 103, 6293–6298.
Tze, L.E., Schram, B.R., Lam, K.P., Hogquist, K.A., Hippen, K.L., Liu,
J., Shinton, S.A., Otipoby, K.L., Rodine, P.R., Vegoe, A.L., et al.
(2005). Basal immunoglobulin signaling actively maintains develop-
mental stage in immature B cells. PLoS Biol. 3, e82. 10.1371/journal.
Uchida, N., Aguila, H.L., Fleming, W.H., Jerabek, L., and Weissman,
I.L. (1994). Rapid and sustained hematopoietic recovery in lethally irra-
diated mice transplanted with purified Thy-1.1lo Lin-Sca-1+ hemato-
poietic stem cells. Blood 83, 3758–3779.
Ueda, Y., Yang, K., Foster, S.J., Kondo, M., and Kelsoe, G. (2004). In-
flammation controls B lymphopoiesis by regulating chemokine
CXCL12 expression. J. Exp. Med. 199, 47–58.
Ueda, Y., Kondo, M., and Kelsoe, G. (2005). Inflammation and the
reciprocal production of granulocytes and lymphocytes in bone mar-
row. J. Exp. Med. 201, 1771–1780.
von Freeden-Jeffry, U., Vieira, P., Lucian, L.A., McNeil, T., Burdach,
S.E., and Murray, R. (1995). Lymphopenia in interleukin (IL)-7 gene-de-
leted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med.
Vosshenrich, C.A., Cumano, A., Muller, W., Di Santo, J.P., and Vieira,
P. (2003). Thymic stromal-derived lymphopoietin distinguishes fetal
from adult B cell development. Nat. Immunol. 4, 773–779.
Vosshenrich, C.A., Cumano, A., Muller, W., Di Santo, J.P., and Vieira,
P. (2004). Pre-B cell receptor expression is necessary for thymic stro-
mal lymhopoietin responsiveness in the bone marrow but not in the
liver environment. Proc. Natl. Acad. Sci. USA 101, 11070–11075.
Wasserman, R., Li, Y.S., Shinton, S.A., Carmack, C.E., Manser, T.,
Wiest, D.L.,Hayakawa, K.,and Hardy, R.R. (1998). Anovelmechanism
for Bcell repertoire maturation based onresponse byBcellprecursors
to pre-B receptor assembly. J. Exp. Med. 187, 259–264.
Welner, R.S., Pelayo, R., Garrett, K.P., Chen, X., Perry, S.S., Sun, X.H.,
Kee, B.L., and Kincade, P.W. (2007). Interferon-producing killer den-
dritic cells (IKDC) arise via a unique differentiation pathway from prim-
itive c-kitHiCD62L+lymphoid progenitors. Blood 109, 4825–4931.
Wen, L., Brill-Dashoff, J., Shinton, S.A., Asano, M., Hardy, R.R., and
Hayakawa, K. (2005). Evidence of marginal-zone B cell-positive selec-
tion in spleen. Immunity 23, 297–308.
Xie, H., Ye, M., Feng, R., and Graf, T. (2004). Stepwise reprogramming
of B cells into macrophages. Cell 117, 663–676.
Ye, M., Iwasaki, H., Laiosa, C.V., Stadtfeld, M., Xie, H., Heck, S., Clau-
sen, B., Akashi, K., and Graf, T. (2003). Hematopoietic stem cells
expressing the myeloid lysozyme gene retain long-term, multilineage
repopulation potential. Immunity 19, 689–699.
Ye, M., Ermakova, O., and Graf, T. (2005). PU.1 is not strictly required
for B cell development and its absence induces a B-2 to B-1 cell
switch. J. Exp. Med. 202, 1411–1422.
Zuniga, E.I., McGavern, D.B., Pruneda-Paz, J.L., Teng, C., and Old-
stone, M.B. (2004). Bone marrow plasmacytoid dendritic cells can
differentiate into myeloid dendritic cells upon virus infection. Nat.
Immunol. 5, 1227–1234.
Immunity 26, June 2007 ª2007 Elsevier Inc.