JEM VOL. 201, June 20, 2005
mutations in immunodominant epi-
tope, a favored trick of rapidly mu-
tating viruses such as HIV or SIV, is
one argument. Others pertain to avoid-
ing holes in the T cell repertoire that
arise due to ageing or to clonal anergy
or exhaustion. As discussed above, a
broader repertoire may provide choices
that allow for the selection of higher
What are the mechanisms that pro-
mote a diverse response? Allison and
colleagues have suggested that the in-
hibitory receptor CLTA-4 serves to at-
tenuate extensive expansion of individ-
ual dominant clones, thereby allowing
other clones to expand and partici-
pate in the response. This attenuation
mechanism may ensure a polyclonal re-
sponse (21). In support of this model,
CTLA-4 expression has been shown to
increase as a function of the number of
cell divisions and high expression levels
of CTLA-4 correlate with inhibition of
clonal expansion. Cytokines might also
broaden the CD8
T response. Al-
though the mechanism is unknown,
exogenous IL-7 administered after im-
munization boosted the response to a
subdominant epitope of the experi-
mental antigen H-Y (22). If diversity is
truly important, there must be several
physiological mechanisms to promote
such a response. These mechanisms re-
main to be fully explored.
Assuming that a multipronged, diverse
T cell response is a
good thing, how might this notion af-
fect future strategies for immunizations?
HIV vaccines are already being de-
signed that include many epitopes from
several genes and many peptide variants
(to cover all possible viral clades). But
this approach remains educated guess-
work, since the exact epitopes pre-
sented in a given patient, and therefore
the breadth of the immunization, are
unknown. To obtain a broad immune
response, additional strategies have been
proposed. Cytokines are being evalu-
ated as adjuvants (22). Engineered im-
munogens incorporating multiple het-
eroclitic peptides that cover an array
of immunodominant and subdominant
epitopes are being used successfully in
vaccine models. Alternatively, tumor-
derived RNA transcribed to cDNA can
be used for immunization, providing a
source of multiple antigens (23), and
virus replicase can be used to amplify
multiple RNA species in “replicon”
vectors (23, 24).
We conclude that the concept of
the phalanx as a mode of attack for the
immune system is outdated. Studies of
the natural immune response to com-
mon viruses like hCMV (1, 2) can
teach us all some important lessons re-
garding the advantages of diverse im-
mune responses. They provide a ratio-
nal basis for vaccines that produce
broad immune responses. This has spe-
cial relevance for the elderly, who need
vaccines most urgently and are least
likely to respond with an efficient and
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Arguments in favor of a multipronged attack
1. Prevents escape mutants in immunodominant epitopes of SIV and HIV
(and other viruses) 25–28
2. Creates choices for the host to select the highest avidity TCRs 20
3. Avoids holes in the repertoire 20
4. Provides backup in case of clonal exhaustion or clonal anergy 29
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