The CD154-CD40 T Cell Costimulation Pathway Is Required for Host Sensitization of CD8+ T Cells by Skin Grafts Via Direct Antigen Presentation

Abstract

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.

Activation of Alloreactive CD8+ T Cells Operates Via CD4-Dependent and CD4-Independent Mechanisms and Is CD154 Blockade Sensitive

“…This complements our previous studies (19,25) and further points toward the CD8 ϩ T cell as the principle target of the CD154 costimulation blockade in organ transplantation.…”

“…We have previously shown that alloreactive CD8 ϩ T cell activation is inhibited in CD154 KO mice (19). This finding provided us with an adoptive cell transfer model system to elucidate putative components in the CD154 costimulation pathway that may lead to activation of alloreactive CD8 ϩ T cells.…”

“…Our recent finding that alloreactive CD8 ϩ T cell activation is defective in CD154 KO mice (19) prompted us to investigate the actual defect that prevents activation of CD8 ϩ T cells in our transplantation model. Our present cell reconstitution experiments document the key defect at the T cell rather than the APC side.…”

“…By employing CD154-deficient (knockout (KO)) mice as recipients of sequential skin and cardiac allografts, and by targeting CD154-CD40 interactions in wild-type (WT) skin-sensitized hosts, we have recently documented the key role of CD154 pathway in host sensitization to alloantigen, and identified CD8 ϩ T cells as the principal targets of CD154 blockade (19). In this study, we took a step further to identify the pathways of alloreactive CD8 activation in terms of CD4 help, and revealed the requirement of CD154 costimulation in both CD4-dependent and CD4-independent mechanisms of alloreactive CD8 T cell activation.…”

Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help

“…By using MHC fully mismatched skin grafts as alloantigen stimulant, we showed that alloreactive CD8 activation may proceed through CD4-dependent and -independent pathways, and that both pathways require CD154 costimulation (7,8). Furthermore, alloantigen-primed CD8 T cells in skin-sensitized recipients become CD154 independent when reactivated by a second skin graft, indicating the functional disparity between naive and memory alloreactive CD8 T cells (9).…”