title: Cutting edge: committed Th1 CD4+ T cell differentiation blocks pregnancy-induced Foxp3 expression with antigen-specific fetal loss.
abstract: Pregnancy stimulates induced Foxp3 expression among maternal CD4(+) T cells with fetal specificity. Although sustained maternal regulatory CD4(+) T cell (Treg) expansion is essential for maintaining fetal tolerance during pregnancy, the necessity for Foxp3(+) cells with fetal specificity remains undefined. In this study, we demonstrate that mitigating Treg differentiation among maternal CD4(+) T cells with a single surrogate fetal specificity elicits Ag-specific fetal loss. Using recombinant Listeria monocytogenes to prime stably differentiated Th1 CD4(+) T cells with fetal I-A(b):2W1S55-68 specificity refractory to pregnancy-induced Foxp3 expression, we show that Ag delivery by cytoplasmic L. monocytogenes causes selective loss of 2W1S(+) offspring through CD4 cell- and IFN-γ-dependent pathways. In contrast, CD4(+) T cells primed by L. monocytogenes restricted from the cell cytoplasm are markedly more plastic for induced Foxp3 expression, with normal pregnancy outcomes. Thus, committed Th1 polarization blocks pregnancy induced Treg differentiation among maternal CD4(+) T cells with fetal specificity and triggers Ag-specific fetal loss.
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xin
authors.forename: James M
authors.initials: JM
authors.lastname: Ertelt
authors.forename: Jared H
authors.initials: JH
authors.lastname: Rowe
authors.forename: Tony T
authors.initials: TT
authors.lastname: Jiang
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Kinder
authors.forename: Vandana
authors.initials: V
authors.lastname: Chaturvedi
authors.forename: Shokrollah
authors.initials: S
authors.lastname: Elahi
authors.forename: Sing Sing
authors.initials: SS
authors.lastname: Way
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D005333:Fetus / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology / Q000502:physiology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007371:Interferon-gamma