Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs

Abstract

Alloreactive memory, unlike naïve, CD8 + T cells resist transplantation tolerance protocols and are a critical barrier to long-term graft acceptance in the clinic. We here show that semi-allogeneic pregnancy successfully reprogrammed memory fetus/graft-specific CD8 + T cells (TFGS) towards hypofunction. Female C57BL/6 mice harboring memory CD8 + T cells generated by the rejection of BALB/c skin grafts and then mated with BALB/c males achieved rates of pregnancy comparable to naive controls. Post-partum fetus/graft-specific CD8 + T cells (TFGS) from skin-sensitized dams upregulated expression of T cell exhaustion (TEX) markers (Tox, Eomes, PD-1, TIGIT, and Lag3). Transcriptional analysis corroborated an enrichment of canonical T exhaustion (TEX) genes in post-partum memory TFGS and additionally, revealed a downregulation of a subset of memory-associated transcripts. Strikingly, pregnancy induced extensive epigenetic modifications of exhaustion-and memory-associated genes in memory TFGS, whereas minimal epigenetic modifications were observed in naive TFGS cells. Finally, post-partum memory TFGS durably expressed the exhaustion-enriched phenotype, and their susceptibility to transplantation tolerance was significantly restored compared to memory TFGS. These findings advance the concept of pregnancy as an epigenetic modulator inducing hypofunction in memory CD8 + T cells that has relevance not only for pregnancy and transplantation tolerance, but also for tumor immunity and chronic infections.