Diversity of the CD4 T Cell Alloresponse: The Short and the Long of It

• Direct-pathway CD4 T cell alloresponses are extremely short lived
• Indirect pathway responses vary markedly according to target alloantigen
• In chronic rejection, MHC class I alloantigen is continually processed and presented
• The kinetics of the alloreactive CD4 T cell response are altered profoundly

SummaryMHC alloantigen is recognized by two pathways: “directly,” intact on donor cells, or “indirectly,” as self-restricted allopeptide. The duration of each pathway, and its relative contribution to allograft vasculopathy, remain unclear. Using a murine model of chronic allograft rejection, we report that direct-pathway CD4 T cell alloresponses, as well as indirect-pathway responses against MHC class II alloantigen, are curtailed by rapid elimination of donor hematopoietic antigen-presenting cells. In contrast, persistent presentation of epitope resulted in continual division and less-profound contraction of the class I allopeptide-specific CD4 T cell population, with approximately 10,000-fold more cells persisting than following acute allograft rejection. This expanded population nevertheless displayed sub-optimal anamnestic responses and was unable to provide co-stimulation-independent help for generating alloantibody. Indirect-pathway CD4 T cell responses are heterogeneous. Appreciation that responses against particular alloantigens dominate at late time points will likely inform development of strategies aimed at improving transplant outcomes.

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