Biology Reference
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IL-7 was required for homeostatic expansion of naïve CD8 and CD4 T cells in
lymphopenic hosts and for CD8 T-cell survival in normal hosts
[72]
. Unlike naïve
T cells, HP memory T cells were largely MHC independent and memory CD8
cells could utilize either IL-7 or IL-15 to undergo HP. In the absence of both IL-7
and IL-15, HP failed to occur. HP of memory CD4 cells is independent of IL-7 and
IL-15 (and also of IL-4)
[73]
. Although HP memory cells responded directly to IL-7
and IL-15, naïve T cells required costimulation by dendritic cell-derived CTKs, and
selectively respond to IL-4
[74]
. All human CD8 T-cell subsets had the ability to
respond to IL-15, which suggests a generic influence of this CTK on CD8 T-cell
homeostasis in humans
[75]
. IL-15 was important for sustained CD8 T-cell prolifera-
tion and accumulation in a lymphopenic setting, as revealed by truncated prolifera-
tion in IL-15 (/) hosts. At the same time, IL-12 enhanced HP by acting directly
on the CD8 T cells, independent of IL-15, suggesting that there are distinct pathways
by which CTKs can regulate HP
[76]
. A novel form of proliferation occurred when
naïve T cells encountered raised levels of IL-2 and IL-15
in vivo
. In this situation,
CD8() T cells underwent massive expansion and rapid differentiation into effector
cells, thus closely resembling the T-cell response to foreign antigens. However, the
responses induced by IL-2/IL-15 were not seen in MHC-deficient hosts, implying
that the responses were driven by self-ligands. Hence, HP of naïve T cells can be
either slow or fast, with the quality of the response to self being dictated by the par-
ticular CTK (IL-7 versus IL-2/IL-15) concerned
[77]
.
In murine allogeneic bone marrow transplantation (BMT) models, two popula-
tions of mature donor T cells could be distinguished: (a) alloreactive T cells with
decreased expression of CD127 (IL-7 receptor alpha chain) and (b) nonalloreactive
T cells, which express CD127 and undergo HP. IL-7 administration increased the HP
of nonalloreactive T cells, but had no effect on alloreactive T cells or the development
of graft-versus-host disease
[78]
. There is a prominent, nonredundant role for IL-7 in
supporting basal HP of CD8()T(M). We propose that homeostatic control of antivi-
ral CD4() and CD8() T-cell memory is fundamentally similar and characterized
by quantitative, rather than qualitative, differences
[79]
. IL-7 is a CTK produced pre-
dominantly by stromal cells of the thymus and bone marrow and is essential for lym-
phopoiesis. IL-7 is of particular importance in lymphopenic conditions. Its expression
is up-regulated in a number of lymphopenic conditions, including marrow ablation
prior to BMT, marrow suppression following chemotherapy, and human immunodefi-
ciency virus (HIV) infection. Plasma IL-7 levels inversely correlate with CD4 T-cell
counts in these conditions. Animal models suggest that IL-7 improves immune recon-
stitution through increasing thymic output and, perhaps more importantly, through
antigen-independent homeostatic-driven proliferation in the periphery
[80]
.
Lymphopenia-induced proliferation depends on low-affinity MHC/self-peptide
complexes and on IL-7 T cells proliferating in lymphopenic hosts. These cells do
not exhibit a unique gene-expression profile, but instead rely on “traditional” signals
for this antigen-independent proliferation, which ultimately results in differentiation
to “authentic” memory cells
[81]
. Memory CD8 T cells retain the ability to respond
to dendritic cell-mediated stimulation after adoptive transfer into either TAP(/)
(MHC class I-deficient) or wild-type mice. Surprisingly, naïve CD8 T cells, which
