Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo

Abstract

Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4−/− but not CD8−/− recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28−/− and a smaller proportion of CD4−/−CD28−/− mice with no effect in CD8−/−CD28−/− recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8+ T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28−/− and CD8−/−CD28−/− recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-γ-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.

Activation drives PD‐1 expression during vaccine‐specific proliferation and following lentiviral infection in macaques

“…Ligation of PD-1 by its receptors, PD-L1 and PD-L2, has been shown to inhibit T cell proliferation and function [19,21,[24][25][26]. Our data indicate that PD-1 up-regulation occurs in the absence of infection on antigenspecific CD8 + T cells early in proliferative responses (Fig.…”

New Insights in CD28‐Independent Allograft Rejection

“…Several studies including data from our own group have pointed to the relative importance of alloantigen-specific effector clone size in mediating graft rejection and sensitivity to immunosuppressive intervention (33,40). The transformation of a naïve T cell to one demonstrating an effector-memory phenotype is characterized by an enhanced CD44 expression and a concomitant reduction in CD62L expression (12). In our skin transplant model, we demonstrated a significant contraction in the size of the CD28-independent effector-memory cell populations (CD44 high CD62L low ) of both CD4…”

“…The relative importance of the CD4 versus the CD8 T cells in allograft rejection has been examined in several models (12). While early studies mainly focused on inhibiting CD4…”

Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells

“…With the separation of these two subpopulations, it will be possible to compare their gene expression profiles and identify candidate molecules involved in the multiple processes responsible for their regulatory activity. In addition, the recently reported selective expression of LAG-3 by stimulated CD4 ϩ CD25 ϩ Treg (that do not express this molecule when quiescent) (17,18) should be considered. Selection based on combinations of PD-1 and LAG-3 expression (on the CD25 ϩ population) should result in successful isolation of the following populations: resting Treg (PD-1 Ϫ ), activated Treg (PD-1 ϩ LAG-3 ϩ ), and activated T cells (PD-1 ϩ LAG-3 Ϫ ; Fig.…”