Tissue-resident memory T cells in human kidney transplants have alloreactive potential

The extent to which tissue-resident memory T (T_RM) cells in transplanted organs possess alloreactivity is uncertain. This study investigates the alloreactive potential of T_RM cells in kidney explants from 4 patients who experienced severe acute rejection leading to graft loss. Alloreactive T cell receptor (TCR) clones were identified in pretransplant blood samples through mixed lymphocyte reactions, followed by single-cell RNA and TCR sequencing of the proliferated recipient T cells. Subsequently, these TCR clones were traced in the T_RM cells of kidney explants, which were also subjected to single-cell RNA and TCR sequencing. The proportion of recipient-derived T_RM cells expressing an alloreactive TCR in the 4 kidney explants varied from 0% to 9%. Notably, these alloreactive TCRs were predominantly found among CD4+ and CD8+ T_RM cells with an effector phenotype. Intriguingly, these clones were present not only in recipient-derived T_RM cells but also in donor-derived T_RM cells, constituting up to 4% of the donor population, suggesting the presence of self-reactive T_RM cells. Overall, our study demonstrates that T cells with alloreactive potential present in the peripheral blood prior to transplantation can infiltrate the kidney transplant and adopt a T_RM phenotype.