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

Area of Science:

• Immunology
• Reproductive Immunology
• Transplantation Immunology

Background:

• Alloreactive memory CD8+ T cells resist transplantation tolerance, hindering long-term graft acceptance.
• Understanding mechanisms to modulate these cells is crucial for improving transplant outcomes.

Purpose of the Study:

• To investigate the impact of semiallogeneic pregnancy on alloreactive memory CD8+ T cells.
• To determine if pregnancy can induce a hypofunctional state in these cells, restoring susceptibility to tolerance protocols.

Main Methods:

• Generation of memory CD8+ T cells via skin graft rejection in female mice.
• Mating sensitized mice to induce semiallogeneic pregnancy.
• Analysis of T cell exhaustion markers, gene expression, and epigenetic modifications in postpartum T cells.
• Assessment of the susceptibility of these reprogrammed cells to transplantation tolerance.

Main Results:

• Semiallogeneic pregnancy successfully reprogrammed memory fetus/graft-specific CD8+ T cells (TFGS) toward hypofunction.
• Postpartum TFGS exhibited upregulated T cell exhaustion (TEX) markers and enriched TEX gene expression.
• Pregnancy induced extensive epigenetic modifications in exhaustion- and memory-associated genes in memory TFGS.
• Reprogrammed TFGS showed restored susceptibility to transplantation tolerance.

Conclusions:

• Pregnancy acts as an epigenetic modulator, inducing hypofunction in memory CD8+ T cells.
• This finding has significant relevance for transplantation tolerance, pregnancy biology, tumor immunity, and chronic infections.