Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity

Abstract

The affinity of a T cell receptor (TCR) binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic antigen and mediate graft rejection. We found that low affinity primed memory CD8+ T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared to high affinity primed memory T cells. Low affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2hi proliferating cells. Low affinity primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low but not high affinity primed animals. These data establish a functional connection between TNF signaling and TCR priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation.

The Significance of Tumor Necrosis Factor Receptor Type II in CD8+ Regulatory T Cells and CD8+ Effector T Cells

“…After encountering with microbial antigen, T cells can differentiate into memory cells to provide long-lasting protection against subsequent pathogens ( 18 , 74 , 75 ). During transplantation, microbe-elicited T memory cells can also cross-react with allogeneic antigen and mediate graft rejection, a process termed allogeneic heterologous immunity.…”

“…During transplantation, microbe-elicited T memory cells can also cross-react with allogeneic antigen and mediate graft rejection, a process termed allogeneic heterologous immunity. TCR affinity is hypothesized to be critically important in the context of allogeneic heterologous immunity ( 18 , 76 , 77 ). Notably, TNFR2 plays an important role for low-affinity-primed memory CD8 + T cells mediating optimum recall responses.…”

“…Notably, TNFR2 plays an important role for low-affinity-primed memory CD8 + T cells mediating optimum recall responses. During heterologous rechallenge, low-affinity-primed memory effectors upregulated TNFR2 surface expression to mediated graft rejection, whereas blockade of TNFR2 significantly attenuated graft rejection and prolonged graft survival ( 18 ). These data indicated that TNFR2 is required and critical for memory CD8 + T cells recovery in immune responses.…”

“…While TNFR1 has been extensively characterized, the biological functions of TNFR2 have remained elusive ( 15 ). There is mounting evidence to suggest that TNFR2 is expressed on and has critical roles in immune cells, including CD4 + regulatory T cells (Tregs) ( 16 ), CD4 + effector T cells (Teffs) ( 4 ), CD8 + Tregs ( 17 ), and CD8 + Teffs ( 18 ). This implies that TNFR2 is involved in various T cell-mediated immune responses.…”

Evolving Approaches in the Identification of Allograft-Reactive T and B Cells in Mice and Humans

“…Theoretically, pMHC multimers can be used to study host T cells that recognize alloantigens both directly and indirectly, depending on whether the MHC in the tetramer matches the haplotype of the graft donor or recipient, respectively. Indirect T cell recognition in mice has been modeled via expression of a model antigen by the donor graft, such as ovalbumin, and tracking of SIINFEKL:K b tetramer-binding CD8 + T cells after transplantation 42,49 . Class II MHC multimers can be used to track CD4 + Tconv and Treg cells but the use of class II MHC multimers has been rarer as they have been technically challenging to generate.…”