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 2 skin graft-reactive CD8⁺ T cell receptor-transgenic tracer populations with high and low affinity for the same peptide-major histocompatibility complex, we explored the conventional paradigm that CD8⁺ T cell avidity maturation occurs through T cell receptor 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 interleukin-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.