Yin, Dengping

Alloreactive memory, unlike naive, CD8 + T cells resist transplantation tolerance protocols and are a critical barrier to long-term graft acceptance in the clinic. We here show that semiallogeneic pregnancy successfully reprogrammed memory fetus/graft-specific CD8 + T cells (T FGS ) toward 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 with naive controls. Postpartum CD8 + T FGS from skin-sensitized dams upregulated expression of T cell exhaustion (T EX ) markers (Tox, Eomes, PD-1, TIGIT, and Lag3). Transcriptional analysis corroborated an enrichment of canonical T EX genes in postpartum memory T FGS and revealed a downregulation of a subset of memory-associated transcripts. Strikingly, pregnancy induced extensive epigenetic modifications of exhaustion- and memory-associated genes in memory T FGS , whereas minimal epigenetic modifications were observed in naive T FGS . Finally, postpartum memory T FGS durably expressed the exhaustion-enriched phenotype, and their susceptibility to transplantation tolerance was significantly restored compared with memory T FGS . 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.

Abstract 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.

Abstract Classic hyperacute rejection is dependent on the activation of the terminal components of complement. Recently, xenoantibodies with limited abilities to activate the classical pathway of complement in vitro have been implicated in the acute vascular rejection of xenografts. It is unclear how these Abs affect their pathogenic activities in vivo. In this study, we demonstrate the ability of an anti-Gal-α1,3Gal (Gal) IgG1, with modest complement-activating abilities in vitro, to induce xenograft rejection. This rejection was dependent on the activation of complement, on FcγR-mediated interactions, and on the presence of NK cells. Inhibition of any one of these factors resulted in the abrogation of IgG1-mediated rejection. In contrast, an anti-Gal IgG3 mAb induced classic, hyperacute rejection that was solely dependent on complement activation. Our observations implicate two types of IgG-mediated rejection; one that is dependent on complement activation, and a second that is uniquely dependent on complement, FcγR, and NK cells.