TY - JOUR
T1 - On CD28/CD40 ligand costimulation, common γ-chain signals, and the alloimmune response
AU - Demirci, Gülçin
AU - Gao, Wenda
AU - Zheng, Xin Xiao
AU - Malek, Thomas R.
AU - Strom, Terry B.
AU - Li, Xian Chang
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2002/5/1
Y1 - 2002/5/1
N2 - 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 γ-chain (γc) 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 γc 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 γc signals for survival, expansion, and functional maturation, whereas in vivo expansion of alloreactive CD4+ T cells is largely γc 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 γc 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 γc signals may be highly effective in certain cytopathic conditions involving activation of both CD4+ and CD8+ T cells.
AB - 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 γ-chain (γc) 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 γc 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 γc signals for survival, expansion, and functional maturation, whereas in vivo expansion of alloreactive CD4+ T cells is largely γc 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 γc 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 γc signals may be highly effective in certain cytopathic conditions involving activation of both CD4+ and CD8+ T cells.
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U2 - 10.4049/jimmunol.168.9.4382
DO - 10.4049/jimmunol.168.9.4382
M3 - Article
C2 - 11970980
AN - SCOPUS:0036568946
SN - 0022-1767
VL - 168
SP - 4382
EP - 4390
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -