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-Chain Signals, and the Alloimmune Response1
* Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215; and
Department of Microbiology and Immunology, University of Miami, Miami, FL 33101
Activation and robust expansion of naive T cells often require T
cell costimulatory signals and T cell growth factors. However, the
precise growth and costimulation requirements for activation and
expansion of CD4+ and CD8+ T cells in vivo in
allograft response are still not clearly defined. In the present study,
we critically examined the role of CD28/CD40 ligand (CD40L)
costimulation and the common 
-chain (c)
signals, a shared signaling component by receptors for all known T cell
growth factors (i.e., IL-2, IL-4, IL-7, IL-9, IL-15, IL-21), in
activation and expansion of CD4+ and CD8+ T
cells in the allogeneic hosts. We found that CD28/CD40L costimulation
and the c signals are differentially involved in
proliferation and clonal expansion of CD4+ and
CD8+ T cells in response to alloantigen stimulation.
CD8+ T cells are highly dependent on the c
signals for survival, expansion, and functional maturation, whereas in
vivo expansion of alloreactive CD4+ T cells is largely
c independent. T cell costimulation via CD28 and CD40L,
however, is necessary and sufficient for activation and expansion of
CD4+ T cells in vivo. In a skin transplant model, blocking
both CD28/CD40L and the c pathways induced prolonged
skin allograft survival. Our study provides critical insights that the
CD4 and CD8 compartments are most likely governed by distinct
mechanisms in vivo, and targeting both costimulatory and
c signals may be highly effective in certain cytopathic
conditions involving activation of both CD4+ and
CD8+ T cells.
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