Tolerance to alloantigens is characterized by low alloreactive T cell responses upon restimulation with donor antigens, a state that can result from deletion of donor-specific T cells, extrinsic regulation, or cell-intrinsic hyporesponsiveness. We previously showed that costimulation blockade-induced transplantation tolerance in mice did not result in complete alloreactive T cell deletion. Instead, these cells persisted long-term and were not ignorant of the graft as they expressed high levels of the memory/activation marker CD44. Whether these T cells differentiated into functional memory cells that were extrinsically controlled by regulatory cells, or were intrinsically dysfunctional was unknown. To address this question, CD4⁺ TCR-Tg T cells (TCR75 cells) recognizing a graft-restricted antigen (peptide from K^d presented by I-A^b) were seeded in C57BL/6 (H-2^b) recipient mice prior to transplantation with BALB/c (H-2^d) hearts and tolerance induction. Five weeks after tolerance had been established, TCR75 cells were re-isolated, analyzed for memory markers by flow cytometry, and sorted so that equal numbers of TCR75 cells from tolerant or sensitized non-tolerant mice were adoptively transferred into new untransplanted C57BL/6 mice. These secondary hosts were then challenged with BALB/c splenocytes to assess recall proliferation of the transferred T cells. TCR75 cells in tolerant mice did not express markers of conventional quiescent memory cells and were impaired in a cell-intrinsic manner in their ability to respond to antigen rechallenge in secondary hosts. Furthermore, early removal of the allograft in tolerized recipients partially restored T cell function, suggesting that persistent antigen drives the T cell-intrinsic hyporesponsive state independently of costimulation blockade. These observations may explain why the most predictive factor of developing tolerance in conventionally immunosuppressed transplant recipients in the clinic is the time elapsed from transplantation. These results may also have important implications for other settings of chronic antigen exposure such as cancer and autoimmunity.

CITATION INFORMATION: Miller M, Wang Y, Chen L, Lei Y, Daniels M, Watkins E, Mora Solano C, McIntosh C, Isaad N, Chong A, Alegre M.-L. Persistent Donor Antigen Leads to Dysfunctional CD4⁺ Memory T Cell Development. Am J Transplant. 2017;17 (suppl 3).

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