{'fraction_non_alphanumeric': 0.023412698412698413, 'fraction_numerical': 0.006150793650793651, 'mean_word_length': 5.3091364205256575, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Induction of fetomaternal tolerance? Suppressing B cells!

Literature Watch 1939 One fascinating model of immune tolerance is pregnancy, because the allogeneic fetus is consistently brought to term by immunocompetent mothers without any immune attack. The exact mechanisms underlying this fetomaternal tolerance remain poorly understood but uncovering those mechanisms will undoubtedly have significant therapeutic implications in the clinic. Pregnancy in general is not an inflammatory state, and the placenta also keeps the allogeneic fetus physically separated from the maternal immune system; however, fetal trophoblasts in the placenta are directly exposed to maternal immune cells, and how they evade the maternal immune system has been an area of active investigation for decades. In animal models where the trophoblasts transgenically express model antigens against maternal T cells—for example, transmembrane chicken OVA (mOVA) or the H-Y minor antigens— the maternal T cells expressing antigen-specific T-cell receptor (TCR) transgenes do respond to those model antigens and proliferate extensively, but they do not elicit attacks on the fetus. Various mechanisms have been proposed to explain this tolerant state, which include the expansion of Foxp3+ Tregs, failure of T effector cell differentiation and induction of regulatory NK cells. Nonetheless, this form of fetomaternal tolerance is conditional, as the postpartum mice carrying the transgenic TCR promptly reject skin grafts that express the model antigens in the same manner as non-pregnant mice. In a recent report in Nature, Rizzuto and colleagues made an interesting discovery, showing that B cells assume a tolerogenic role in fetomaternal tolerance, where they prevent maternal T cells from acquiring an Th1 type of effector program and direct them into a tolerant state. Clearly, their findings provide a new perspective on the mechanisms of fetomaternal tolerance. The authors initially bred male mOVA transgenic mice with female mice that were deficient in antigen-presenting cells, including dendritic cells, B cells or those with impaired antigen-presenting capacities, such as those with an irrelevant transgenic BCR or conditional deletion of MHC class II in B cells. The pregnant mice were then adoptively transferred with CFSE-labeled and mOVA-specific OT-II (CD4+) and OT-I (CD8+) T cells, which recognize fetuses that express the mOVA transgene. They found that, while dendritic cells are critical for proliferation of OT-I cells, host B cells are required for driving proliferation of OT-II cells in response to mOVA in an MHC class II-restricted manner. Similar to the results of published studies, the OT-I cells are dysfunctional against fetal mOVA stimulation and therefore lack effector functions. Interestingly, unlike the H-Y and 2W1S model antigens that often induce marked de novo expansion of Foxp3+ Tregs, the mOVA on fetal trophoblasts fail to convert OT-II cells into Foxp3+ Tregs in vivo in the pregnant mice, Moreover, depletion of maternal Tregs does not produce pregnancy failure, suggesting that the fetomaternal tolerance achieved in this model is independent of Tregs. The authors then pursued the question of why B cells promote proliferation of OT-II cells but fail to support their effector functions against fetal mOVA antigen. They found that in pregnant mice bearing wild-type fetuses, challenge with soluble chicken OVA (cOVA) together with poly(I:C) adjuvants and an agonistic anti-CD40 Ab induced robust Th1 differentiation of OT-II cells, but this Th1 differentiation was not observed in those bearing mOVAtransgenic fetuses, suggesting that presentation of mOVA by host B cells induces robust tolerance of OT-II cells, even under strong Th1-inducing conditions. Mechanistically, the authors showed that mOVA is more heavily glycosylated than cOVA. Importantly, mOVA-associated glycans contain α2,6-linked and α2,3linked sialic acids that strongly inhibit T cell activation upon binding to the transmembrane proteins CD22 and Siglec-G on B cells. In fact, CD22 is primarily expressed by B cells, and both CD22 and Siglec-G depend on the kinase LYN to suppress B cell activities. Further studies using CD22 or LYN knockout mice confirmed that the mOVA on fetal trophoblasts inhibits B cells through LYN-dependent Siglec signaling, which in turn restrains Th1 differentiation of OT-II cells. One intriguing finding is that the LYN knockout female mice did not experience any fetal loss, suggesting that additional pathways may exist to prevent T cells from acquiring effector features at the maternal-fetal interface. Together, this study provides strong evidence that B cells are the primary drivers of CD4+ T cell activities at the maternal-fetal interface. The trophoblast-derived glucans shut off B cells and therefore restrain T effector functions, leading to the establishment of fetomaternal tolerance. Further studies into the immune regulatory functions of B cells are warranted in tolerant models beyond pregnancy.