CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade

Abstract

Blockade of costimulatory signals is a promising therapeutic target to prevent allograft rejection. In this study, we sought to characterize to what extent CTLA-4 engagement contributes to the development of transplantation tolerance under the cover of CD40/CD40L and CD28/CD86 blockade. In vitro, we found that inhibition of the primary alloresponse and induction of alloantigen hyporesponsiveness by costimulation blockade was abrogated by anti-CTLA-4 mAb. In addition, regulatory CD4+CD25+ T cells (TREG) were confirmed to play a critical role in the induction of hyporesponsiveness by anti-CD40L and anti-CD86 mAb. Our data indicated that CTLA-4 engagement is not required for activation or suppressor function of TREG. Instead, in the absence of either CTLA-4 signaling or TREG, CD8+ T cell division was enhanced, whereas the inhibition of CD4+ T cell division by costimulation blockade remained largely unaffected. In vivo, the administration of additional anti-CTLA-4 mAb abrogated anti-CD40L- and anti-CD86 mAb-induced cardiac allograft survival. Correspondingly, rejection was accompanied by enhanced allograft infiltration of CD8+ cells. We conclude that CTLA-4 signaling and TREG independently cooperate in the inhibition of CD8+ T cell expansion under costimulation blockade.

T-Cell Costimulation and Coinhibition in Atherosclerosis

“…When PD-1 binds its ligands simultaneously with TCR binding antigen, the ITSM becomes phosphorylated. Protein tyrosine phosphatases (SHP-2 and perhaps SHP-1) may bind to the phosphorylated ITSM, and block kinase-dependent signals induced by TCR signaling 54. A role for the ITIM is not clear.…”

CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

“…53 Blockade of CTLA-4 signaling has also been shown to negatively affect the induction of tolerance in other models using costimulatory blockade, but in these cases the effects were attributed to enhanced CD8 T-cell responses. 65,66 Mixed chimerism could not be established in mice with only CD80/86 Ϫ/Ϫ (DKO) hematopoietic cells. However, in animals in which all T cells were derived from DKO BMCs whereas most non-T cells originated from TCR␤ Ϫ/Ϫ marrow and expressed normal levels of CD80/86, mixed allogeneic chimerism was readily achieved.…”

CTLA-4 and CD4+CD25+ Regulatory T Cells Inhibit Protective Immunity to Filarial Parasites In Vivo

“…ϩ Treg cells (34,35,47). Although neutralizing CTLA-4 alone during an established L. sigmodontis infection did not promote protective immunity, when CTLA-4 neutralization was performed in combination with depletion of CD25…”

“…Indirect mechanisms include stimulating the production of the regulatory cytokine TGF-␤ (29 -31) and "back signaling" through CD80/ CD86, causing up-regulation of indoleamine 2,3-dioxygenase resulting in the development of DC with inhibitory properties (32,33). Although many of the regulatory roles of CTLA-4 are independent of and can be complementary to Treg cells (34,35), CTLA-4 is also associated with the development and suppressive function of Treg cell responses (23,24,36,37).…”