New insights into T-cell cosignaling in allograft rejection and survival

Stimulatory and inhibitory receptor signaling (cosignaling) on T cells is a critical component of T-cell responses that mediate graft rejection. The blockade of cosignaling pathways is an attractive strategy for preventing allogeneic T-cell responses. Here, we review the new studies that provide critical insight into the well studied CD28-CTLA-4 and CD40-CD40L cosignaling pathways, as well as the identification of novel cosignaling receptors that play a role in allogeneic T-cell responses.

Recently, it has been appreciated that the CD28-CTLA-4 pathway has unique roles on specific T-cell subsets, particularly on forkhead box P3 (FoxP3)+ regulatory T cell (Treg) and T helper 17 (Th17) cells. New insight has been provided into the mechanism by which CD40-CD154 blockade elicits FoxP3+ Treg conversion and memory T cells elicit CD40-independent alloantibody responses. Finally, several novel cosignaling pathways have been demonstrated to be important to graft-specific T cells, including CD160, signaling lymphocytic activation molecule family member 2B4, T-cell Ig mucin 4, and the Notch receptor.

Recent work has provided more granular understanding of the CD28-CTLA-4 and CD40-CD154 pathways on T-cell subsets, and provided important insight into the generation and maintenance of FoxP3+ Treg. This information, as well as the characterization of novel transplantation-relevant cosignaling pathways, has implications for the modulation of alloreactive T-cell responses.