Pregnancy dedifferentiates memory CD8+ T cells into hypofunctional cells with exhaustion-enriched programs
Jared M. Pollard, Grace Hynes, Dengping Yin, Malay Mandal, Fotini Gounari, Maria-Luisa Alegre, Anita S. Chong
Jared M. Pollard, Grace Hynes, Dengping Yin, Malay Mandal, Fotini Gounari, Maria-Luisa Alegre, Anita S. Chong
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Research Article Immunology Transplantation

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

Abstract

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 (TFGS) 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+ 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 TEX genes in postpartum memory TFGS 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 TFGS, whereas minimal epigenetic modifications were observed in naive TFGS. Finally, postpartum memory TFGS durably expressed the exhaustion-enriched phenotype, and their susceptibility to transplantation tolerance was significantly restored compared with 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.

Authors

Jared M. Pollard, Grace Hynes, Dengping Yin, Malay Mandal, Fotini Gounari, Maria-Luisa Alegre, Anita S. Chong

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Figure 6

Pregnancy alters the chromatin state of memory but not naive OVA-specific TFGS.

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Pregnancy alters the chromatin state of memory but not naive OVA-specifi...
(A and B) TFGS subsets were acquired and sorted for ATAC-Seq as in Figure 2A. Box plots visualizing chromatin accessibility at DEGs unique to P vs. N (A) or unique to R+P vs. R (B). P values (for A and B) were determined by Welch’s 2-tailed t test. (C and D) UMAP and box plots of chromatin accessibility at the 196 DEGs shared by P and R+P vs. R TFGS. Data acquired from ≥ 2 biologically independent experiments with n = 3–4 per group. P values (for D) were determined by Welch’s 2-tailed t test. (E) Bar plots visualizing the mean fold-change of distal ATAC-Seq peaks within 0–50 kb (left) or 50–100 kb (right) of the TSS of shared pregnancy-induced DEGs. P vs. N TFGS (blue) or R+P vs. R TFGS (red). P values (for E) were determined by Welch’s 1-tailed t test. (F–K) ATAC-Seq tracks at the Tox, Maf, and Satb1 loci (F–H), and Ccl5, Ifngr1, and Prf1 (I–K). Peaks uniquely induced in R and reversed in R+P TFGS are highlighted in gray. Each dot in box plots or UMAP indicates an individual mouse. **P < 0.01, ***P < 0.001; ****P < 0.0001.