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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 (TFGS) towards hypofunction in a manner that is mechanistically distinct from naive TFGS. Post-partum memory TFGS 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 TFGS reminiscent of T cell exhaustion. Strikingly, at loci transcriptionally modified in both naive and memory TFGS during pregnancy, chromatin remodeling was observed exclusively in memory and not naive TFGS. 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.

Pregnancy is an immunological paradox, where the maternal immune system develops tolerance to a semi-allogeneic fetus, yet pregnancy is a major sensitizing event in clinical transplantation. We previously reported that pregnancy robustly tolerizes fetus-specific T cells, allowing for the spontaneous acceptance of fetus-matched allografts when B cells and alloantibodies are absent at the time of transplantation(1). In this study, we report that mice sensitized to 2WOVA.B/c allogeneic skin grafts (Memory) underwent successful pregnancies comparable to Naïve mice when mated with 2WOVA.B/c males. We utilized a high-dimensional multi-omics approach to characterize post-partum (PP) fetus-specific T cells from Naïve or Memory mice after semi-allogeneic pregnancies. Strikingly, pregnancy induced fetus-specific naïve and memory T cells to achieve a nearly identical phenotype, characterized by upregulation of co-inhibitory molecules FR4, CD73, PD1, and CTLA4 in CD4+FoxP3- Tconvs and upregulated PD-1, FR4 and Lag3 in CD8+ T cells. We confirmed that naïve and memory PP CD8+ T cells acquired similar transcriptional profiles via RNA-Seq; unexpectedly, pregnancy induced profound epigenetic modifications in memory, but not naïve, CD8+ T cells. In vitro studies indicated reduced TNF aproduction by memory PP CD4+ and CD8+ T cells, and experiments examining their response to fetus-matched allografts are ongoing. Our studies suggest that significant epigenetic imprinting is necessary to constrain memory T cells to preserve fetal viability during semi-allogeneic pregnancy. These findings may provide insights into controlling antigen-specific memory T cells, a major barrier to clinical transplant success