Low Affinity CD8+ CD45RBhigh TNF-Producing TCM Are Potently Alloreactive Against High Affinity Antigen in a Model of T Cell Receptor Cross-Reactive Heterologous Immunity.

Abstract

Memory T cells primed against microbial antigen can cross-react with allogeneic antigen and mediate graft rejection, a process termed heterologous immunity. This scenario requires the T cell receptor (TCR) to recognize both the priming microbial peptide:MHC (pMHC) and an allogeneic pMHC complex, distinct binding interactions that likely have different magnitudes of TCR:pMHC affinity. However, the role that TCR affinity plays during heterologous immunity is unknown. To investigate the impact of TCR affinity during heterologous immune responses, we utilized a model in which transgenic CD8+ T cells are primed via pathogen infection with either high affinity or low affinity antigen, and are subsequently challenged with a skin allograft that constitutively expresses high affinity antigen. Our results demonstrate that infections with high and low affinity antigen generated a similar frequency of KLRG-1lowCD127high memory precursor cells. However, compared to high affinity memory cells, a greater proportion of low affinity memory cells became CD44highCD62Lhigh TCM. Furthermore, the low affinity memory population contained significantly more TNF+ and TNF+IFN-g+ double producer cells when rechallenged with high affinity antigen. Surprisingly, low affinity primed memory CD8+ T cells rejected skin allografts with faster kinetics than high affinity memory CD8+ T cells and were resistant to a costimulation/integrin blockade regimen. We next sought to understand the mechanistic basis underlying this increased potency of low affinity memory CD8+ T cells. High and low affinity memory cells expressed similar levels of TCR, CD8, and CD5; however, low affinity memory cells were predominantly CD45RBhigh, suggesting that CD45RB expression may tune low affinity memory CD8+ T cells to optimally respond to antigen with a broad range of affinity. These studies reveal an important role for low affinity memory CD8+ T cells during graft rejection in the context of heterologous immunity, and identify the phenotypic and functional characteristics associated with their increased potency in vivo.