Pregnancy programs epigenetic and transcriptional exhaustion in memory CD8⁺ T cells

Alloreactive memory T cells, unlike naive T cells, fail to be restrained by transplantation tolerance protocols or regulatory T cells, and therefore represent a critical barrier to long-term graft acceptance. Using female mice sensitized by rejection of fully-mismatched paternal skin allografts, we show that subsequent semi-allogeneic pregnancy successfully reprograms memory fetus/graft-specific CD8⁺ T cells (T_FGS) towards hypofunction in a manner that is mechanistically distinct from naive T_FGS. Post-partum memory T_FGS were durably hypofunctional, exhibiting enhanced susceptibility to transplantation tolerance induction. Furthermore, multi-omics studies revealed that pregnancy induced extensive phenotypic and transcriptional modifications in memory T_FGS reminiscent of T cell exhaustion. Strikingly, at loci transcriptionally modified in both naive and memory T_FGS during pregnancy, chromatin remodeling was observed exclusively in memory and not naive T_FGS. These data reveal a novel link between T cell memory and hypofunction via exhaustion circuits and pregnancy-mediated epigenetic imprinting. This conceptual advance has immediate clinical relevance to pregnancy and transplantation tolerance.