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Differential Role of Naïve and Memory CD4+ T‐Cell Subsets in Primary Alloresponses

The T cell response to major histocompatibility complex (MHC) alloantigens occurs via two main pathways. The direct pathway involves the recognition of intact allogeneic MHC:peptide complexes on donor cells and provokes uniquely high frequencies of responsive T cells. The indirect response results from alloantigens being processed like any other protein antigen and presented as peptide by autologous antigen‐presenting cells. The frequencies of T cells with indirect allospecificity are orders of magnitude lower and comparable to other peptide‐specific responses. In this study, we explored the contributions of naïve and memory CD4+ T cells to these two pathways. Using an adoptive transfer and skin transplantation model we found that naive and memory CD4+ T cells, both naturally occurring and induced by sensitization with multiple third‐party alloantigens, contributed equally to graft rejection when only the direct pathway was operative. In contrast, the indirect response was predominantly mediated by the naïve subset. Elimination of regulatory CD4+CD25+ T cells enabled memory cells to reject grafts through the indirect pathway, but at a much slower tempo than for naïve cells. These findings have implications for better targeting of immunosuppression to inhibit immediate and later forms of alloimmunity.