The effect of pregnancy on the immune system was first reported by J.J.Rodd in 1959 when he described peripartum women experiencing an increased number of blood transfusion reactions as a result of the production of anti-HLA antibodies during pregnancy.1 Following re-encounter of fetus-matched HLA during organ transplantation, anti-HLA antibodies rapidly increase as a result of recall responses by pregnancy-induced memory B cells. This pregnancy-induced humoral sensitization is a major contributor to the sex disparity in organ transplantation.2 Paradoxically, despite the pathogenic effects of fetus HLA-specific antibodies to transplanted organs, these antibodies do not preclude successful multiple pregnancies with the same partner.
The mechanisms of immunological tolerance to semiallogenic offspring antigens despite repeated pregnancies‚ but rejection of offspring-matched allografts remain incompletely defined. Multiple mechanisms‚ including systemic and local uterine microenvironment factors that mediate successful semiallogeneic pregnancies‚ have been identified. Systemic changes comprise increased fetus-specific regulatory T cells, induction of anergy, and exhaustion of fetus-specific CD4+ Tconvs and CD8+ T cells.3,4 Local uterine effects include the trapping of dendritic cells within the decidua and epigenetic silencing of chemokine genes in decidual stromal cells that prevent activated T cells from accumulating at the maternal–fetal interface.5 Many of these mechanisms result in suppressed T-cell responses, but how pregnancy regulates humoral responses is less well understood.
In a recent publication in Nature, Rizzuto et al6 report that trophoblast-derived antigens are critical in suppressing fetal-specific B cells and CD4 T cells, thus providing new insights into the protolerogenic networks that are at play during pregnancy.6 They utilized a murine preclinical model whereby nontransgenic C57BL/6 female mice were mated with C57BL/6 male mice bearing the Act-mOVA transgene. The trophoblast and approximately 50% of the concepti express transmembrane OVA, which is shed into the maternal circulation, thus enabling the capture and presentation of OVA peptides by the maternal antigen-presenting cells to CD4+ and CD8+ T cells. OVA-specific OT-I and/or OT-II TCR transgenic T cells were adoptively transferred to the pregnant mice at mid-gestation, and some mice were also immunized with Th1 polarizing adjuvant polyinosinic:polycytidylic acid [poly(I:C)], agonistic anti-CD40 antibodies, and chicken OVA protein. OT-II cells expanded but did not acquire an antigen-experienced CD44hiCD62Llo phenotype and did not produce interferon-γ, thus representing a suppressed CD4+ T-cell phenotype that was acquired independently of FoxP3+ regulatory T cells during pregnancy.
As the suppression of T-cell responses to OVA was not observed for CD8+ T-cell responses, the authors hypothesize that different antigen-presenting cells (APCs) were engaging with CD4+ versus CD8+ T cells. By utilizing mice that lacked dendritic cells (flt3l−/− and Batf3−/−) and B cells (μMT mice), Rizzuto et al6 demonstrated that B cells presented OVA to CD4+ T cells, whereas dendritic cells interacted with OT-I CD8+ T cells. The observation that OVA-specific B cells sensed circulating OVA by mid-gestation was confirmed by tracking OVA-specific B cells using fluorescently conjugated OVA tetramers and observed to upregulate CD95 and MHCII. OVA-specific B cells did not differentiate into germinal center GL7+CD95+ B cells suggesting the possibility that trophoblast secreted OVA was suppressing OVA-specific B cells and subsequently, T-cell. To test the hypothesis that trophoblast-derived OVA was suppressive for B cells, whereas chicken-derived OVA was immunogenic, a biochemical analysis was performed, which revealed that trophoblast-derived OVA was extensively decorated by glycans containing terminal α(2,6)-linked and α(2,3)-linked sialic acids. Because sialic acids are ligands for the inhibitory receptors CD22 and Siglec-G expressed on B cells, the authors reasoned that highly sialylated glycan-decorated OVA entering B-cell follicles bound to CD22 and induced CD22–Lyn signaling in B cells.7 This signaling pathway resulted in reduced expression of the costimulatory molecules CD80 and CD86 on B cells that may contribute to reduced OT-II responses. Indeed, OVA-specific B cells from pregnant CD22- or Lyn-deficient mice exhibited an augmented accumulation of OVA-specific B cells and expression of germinal center phenotype compared with pregnant WT controls. Furthermore, priming of OT-II T cells was enhanced in Lyn-deficient mice during OVA+ pregnancy together with chicken OVA/adjuvant immunization‚ and they acquired an antigen-experienced CD44hiCD62Llo phenotype and enhanced IFNγ-production.
Those observations point to a novel mechanism that enables the suppression of fetal-specific CD4+ T-cell responses‚ and thus‚ successful semiallogeneic pregnancy, by the secretion of highly sialylated fetal antigens that suppress antigen-specific B cells and subsequently antigen-specific CD4+ T cells (Figure 1). Complementary to Rizzuto et al, Erickson et al8 recently reported that anti-Listeria antibodies produced during pregnancy and vertically transmitted through breast milk required posttranslation modification by sialic acid acetyl esterase to effect protection against Listeria infection in neonatal mice. The deacetylation of terminal sialic acid residues exposes sialic acid residues on IgG, thus allowing IgG binding to CD22 on a select subset of B10-like cells and inhibiting their production of IL-10. The consequence of reduced IL-10 production is suboptimal protective T-cell responses to intracellular Listeria infection in the neonate. Taken together, studies by Rizzuto et al6 and Erickson et al8 underscore a common theme that the exposed sialic acid residues on trophoblast-derived antigens or IgG generated during pregnancy may exquisitely titrate the levels of B cell and CD4+ T-cell activation.
These novel observations raise new questions for future investigation. For example, are the highly sialylated antigens only produced by trophoblast cells or also by the fetus? Is degree of sialylation on fetal antigens and IgG reduced at the time of parturition or in the postpartum period to ensure the production of functionally protective antibodies that minimally engage CD22? In support of this possibility, we previously reported that the adoptive transfer of sera from early postpartum mice prevented the tolerance of fetus-matched heart allografts by costimulation blockade (anti-CD154 or CTLA-4Ig). These antibodies also overrode pregnancy-induced T-cell–mediated spontaneous acceptance of fetus-matched grafts in B cell-deficient postpartum recipients.9 Finally‚ and with relevance for solid organ transplantation, these observations suggest that enhancing the level of sialylation on proteins or agonistic anti-CD22 antibodies might represent effective approaches for suppressing donor-specific B-cell responses in sensitized transplant recipients harboring memory B cells.10
1. van Rood JJ, Eernisse JG, van Leeuwen A. Leucocyte antibodies in sera from pregnant women. Nature. 1958;181:1735–1736.
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9. Suah AN, Tran DV, Khiew SH, et al. Pregnancy-induced humoral sensitization overrides T cell tolerance to fetus-matched allografts in mice. J Clin Invest. 2021;131:140715.
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