The CD154-CD40 T cell costimulation pathway is required for host sensitization of CD8(+) T cells by skin grafts via direct antigen presentation.
Although the CD154-CD40 T cell costimulation pathway has been shown to mediate alloimmune responses in normal recipients, little is known about its role in sensitized hosts. In this work, by using novel models of cardiac allograft rejection in skin-sensitized CD154- and CD40-deficient mice, we reaffirm the key role of CD154-CD40 signaling in host sensitization to alloantigen in vivo. First, we identified CD8(+) T cells as principal effectors in executing accelerated rejection in our model. Disruption of CD154-CD40 signaling in recipients at the T cell side (CD154-deficient) but not at the APC side (CD40-deficient) abrogated accelerated (<2 days) rejection and resulted in long-term (>100 days) graft survival. This suggests that the CD154-dependent mechanism in host CD8(+) T cell sensitization operates via the direct Ag presentation. Then, in comparative studies of alloimmune responses in CD154-deficient and wild-type recipients, we showed that, although alloreactive B cell responses were inhibited, alloreactive T cell responses were down-regulated selectively in the CD8(+) T cell compartment, leaving CD4(+) T cells largely unaffected. This unique alteration in host alloreactivity, seen not only in peripheral lymphocytes but also in allograft infiltrate, may represent the key mechanism by which disruption of CD154-CD40 signaling prevents sensitization to alloantigen in vivo and leads to long-term allograft survival.
Dumont-University of California Transplant Center, University of California School of Medicine, Los Angeles, CA 90095, USA.
Yuan
Y
Zhai
Xiu-Da
XD
Shen
Feng
F
Gao
Ana J
AJ
Coito
Barbara A
BA
Wasowska
Alan
A
Salama
Isabela
I
Schmitt
Ronald W
RW
Busuttil
Mohamed H
MH
Sayegh
Jerzy W
JW
Kupiec-Weglinski
D000818:Animals; D017951:Antigen Presentation; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D006085:Graft Survival; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology*; D014184:Transplantation, Homologous
D019013:CD40 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D023201:CD40 Ligand