Immunological yin-yang after pregnancy

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Science Immunology  05 Mar 2021:
Vol. 6, Issue 57, eabh3186
DOI: 10.1126/sciimmunol.abh3186


Pregnancy induces both humoral sensitization and T cell tolerance to paternal tissues.

Pregnancy is a recognized immunotolerant state in that semi-allogeneic fetuses are not rejected, but it also sensitizes post-partum females to potential future exposure of those same alloantigens in the form of solid organ transplants. To better understand this dichotomy, Alegre, Chong, and co-workers developed a system combining pregnancy with heterotopic heart transplant and evaluated endogenous antigen specific conventional (Tconv) and regulatory (Treg) T cell responses as well as allospecific B cell responses to paternal derived antigens. MHC-mismatched mice were mated, thus exposing them to male-derived antigens, and then females were transplanted with semi-allogeneic F1 tissue. The F1 tissues are semi-allogeneic as they derive 50% of their genetic material from the female, who in these experiments is both the mother and the recipient of transplanted tissues. Specifically, C57BL/6 (H-2b) female mice were mated with Balb/c (H-2d) males expressing a 2W1S-OVA transgene; 2W1S-OVA includes both MHC class I and II restricted peptides. The females were then transplanted with F1 tissues (H-2b/d; 2W1S-OVA) 45 to 60 days post-partum. Tetramers were used to characterize self-restricted CD4+ (2W1S:I-Ab), CD8+ (OVA:Kb), and alloreactive B (MHC Kd, Ld, I-Ed) cells in the post-partem, post-transplant mice.

Pregnancy alone led to the relative expansion of 2W1S:I-Ab specific Treg with increased CD73 and CTLA-4. There was an expected robust anti-paternal antibody response that was T cell co-stimulation dependent. Post-partum females of semi-allogeneic pregnancies treated with co-stimulation blockade and donor splenocyte transfusion had prolonged cardiac allograft survival but did not display long-term tolerance to semi-allogeneic heart transplants. Interestingly, post-partum females genetically lacking both B cells and circulating anti-fetus antibodies spontaneously accepted F1 heart transplants, whereas B cells unable to secrete IgG were sufficient to prevent the tolerant phenotype. Finally, anti-CD20 mediated depletion of B cells in sensitized post-partum mothers led to prolonged heart transplant survival and correlated with a decrease in interferon gamma from OVA:Kb-specific CD8 T cells. These data suggest that B cells primed by pregnancy have a proinflammatory or antigen-presentation function in addition to their production of anti-fetus antibodies. These findings shed important light on pregnancy-related immune responses and suggest that multiparous mothers may be prone to development of T cell tolerance to offspring-matched organs in the absence of persisting fetal-specific antibodies and B cells.

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