Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero

Mold, Jeff E.; Michaëlsson, Jakob; Burt, Trevor D.; Muench, Marcus O.; Beckerman, Karen; Busch, Michael P.; Lee, Tzong‐Hae; Nixon, Douglas F.; McCune, Joseph M.

doi:10.1126/science.1164511

Cited by 710 publications

(777 citation statements)

References 24 publications

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“…31 In line with this report, our results show that also minor H antigen-specific CD8 ϩ T CTL may be (partly) functionally tolerized in mother and child as a consequence of exposure to minor H alloantigens through pregnancy. The minor H antigen-specific CD8 ϩ T REG identified in our study may, like their CD4 ϩ CD25 high counterparts, persist for decades.…”

Section: Discussionsupporting

confidence: 90%

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Halteren

Jankowska‐Gan

Joosten

et al. 2009

Blood

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Bidirectional cell transfer during pregnancy frequently leads to postpartum persistence of allogeneic cells and alloimmune responses in both the mother and in her offspring. The life-long consequences of naturally acquired alloimmune reactivity are probably of importance for the outcome of allogeneic stem cell transplantation. We investigated the presence of CD8 pos minor histocompatibility (H) antigen-specific cytotoxic T lymphocytes (T CTL ) and CD8 pos minor H antigen-specific T regulator cells (T REG ) in peripheral blood cells obtained from 17 minor H antigen-disparate mother-offspring pairs. Absence of minor H antigen-specific T REG , as marked by the feasibility to expand T CTL from isolated tetramer pos populations, was observed in 6 mothers and 1 son. The presence of minor H alloantigen-specific T REG was observed in 4 mothers and 5 sons.These T REG were detected within isolated tetramer dim staining fractions and functioned in a CTLA-4-dependent fashion. Our study indicates that both T CTL and T REG mediated alloimmunity against minor H antigens may be present in healthy female and male hematopoietic stem cell donors, potentially influencing graftversus-host reactivity in different ways.

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Section: Discussionsupporting

confidence: 90%

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Halteren

Jankowska‐Gan

Joosten

et al. 2009

Blood

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“…The functional significance of these maternal leukocytes during normal gestation is presently unclear. In humans, maternal-fetal cellular trafficking may contribute to fetal immune development and maternal-fetal tolerance, inducing the fetus to develop Tregs against maternal antigens (19). Changes in the levels of maternal-fetal cellular trafficking have been reported to correspond with maternal-fetal histocompatibility in the mouse model, suggesting that cellular trafficking has implications for maternal-fetal tolerance (37,40).…”

Section: Discussionmentioning

confidence: 99%

“…Although the functional significance of this phenomenon is unclear, there is speculation that microchimerism resulting from this trafficking may be involved in the pathogenesis of autoimmune disease or in the tissue response to injury (17,18). In humans, the presence of microchimeric maternal cells in fetuses was recently shown to induce fetal Tregs against NIMAs (19), suggesting that the fetus can develop dominant tolerance to foreign antigens encountered during development. However, the role of trafficking maternal leukocytes in fetal transplantation has not, to our knowledge, been studied.…”

Section: Introductionmentioning

confidence: 99%

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Nijagal¹,

Wegorzewska²,

Jarvis³

et al. 2011

J. Clin. Invest.

125

133

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Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell-deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.

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“…Among these are the actions of the powerful T regulatory (Treg) cell that has the ability to negatively regulate major portions of the cellular immune system 6. During pregnancy, the mother develops Treg specificity for fetal antigens and, similarly, the fetus develops Tregs with specificity for non‐inherited maternal antigens 1, 2, 3. During preeclampsia, there is significant evidence demonstrating markers of maternal immune activation as part of the disease 7.…”

Section: Introductionmentioning

confidence: 99%

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Loewendorf

Nguyen

Yesayan

et al. 2015

American J Rep Immunol

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ProblemPreeclampsia affects 3–17% of pregnancies worldwide and has serious consequences for both the mother and the fetus. As maternal–fetal immune tolerance is bidirectional, fetal immunopathology may play a significant role in the pathogenesis of pregnancy disorders. Nevertheless, the impact of preeclampsia on the fetal immune system is unclear.Method of studyIn this case–control study, we examined the phenotype of innate and adaptive immune cells from the cord blood of 3rd trimester babies born to healthy mothers and compared them to cord blood from 3rd trimester babies born to mothers with symptomatic preeclampsia.ResultsThe ratio of CD56hi CD16− non‐activated/regulatory NK cells to CD56lo CD16+ activated/effector NK cells as well as the proportion of CD4+ T cells was significantly decreased in the cord blood of babies born to preeclamptic mothers. The percentage of FoxP3+ Treg, especially the FoxP3lo populations (resting Treg and cytokine Treg), were significantly reduced. Importantly, this reduction in FoxP3+ Treg affected the ratio of CD8+ effector T cells per FoxP3+ Treg in the cord blood of babies born to preeclamptic mothers.ConclusionThese observations indicate that there are significant fetal immune system derangements during preeclampsia.

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Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero

Cited by 710 publications

References 24 publications

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

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