Low Affinity CD8+ T Cells Provide Interclonal Help to High Affinity CD8+ T Cells to Augment Alloimmunity

Following solid organ transplantation, small precursor populations of polyclonal CD8+ T cells specific for any graft-expressed antigen preferentially expand their high affinity clones. This phenomenon, termed ‘avidity maturation’, results in a larger population of CD8+ T cells with increased sensitivity to alloantigen, posing a greater risk for graft rejection. Using a mouse model of minor-mismatched skin transplantation, coupled with the tracking of two skin graft-reactive CD8+ TCR-transgenic (Tg) tracer populations with high and low affinity for the same peptide-major histocompatibility complex (pMHC), we explored the conventional paradigm that CD8+ T cell avidity maturation occurs through T-cell receptor (TCR) affinity-based competition for cognate antigen. Our data revealed ‘interclonal CD8-CD8 help’, whereby lower/intermediate affinity clones help drive the preferential expansion of their higher affinity counterparts in an IL-2/CD25-dependent manner. Consequently, the CD8-helped high affinity clones exhibit greater expansion and develop augmented effector functions in the presence of their low affinity counterparts, correlating with more severe graft damage. Finally, interclonal CD8-CD8 help was suppressed by costimulation blockade treatment. Thus, high affinity CD8+ T cells can leverage help from low affinity CD8+ T cells of identical specificity to promote graft rejection. Suppressing provision of interclonal CD8-CD8 help may be important to improve transplant outcomes.