title: T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2.
abstract: Foxp3(+) regulatory T (Treg) cells limit inflammatory responses and maintain immune homeostasis. Although comprised of several phenotypically and functionally distinct subsets, the differentiation of specialized Treg cell populations within the periphery is poorly characterized. We demonstrate that the development of T-bet(+) Treg cells that potently inhibit T helper 1 (Th1) cell responses was dependent on the transcription factor STAT1 and occurred directly in response to interferon-γ produced by effector T cells. Additionally, delayed induction of the IL-12Rβ2 receptor component after STAT1 activation helped ensure that Treg cells do not readily complete STAT4-dependent Th1 cell development and lose their ability to suppress effector T cell proliferation. Thus, we define a pathway of abortive Th1 cell development that results in the specialization of peripheral Treg cells and demonstrate that impaired expression of a single cytokine receptor helps maintain Treg cell-suppressive function in the context of inflammatory Th1 cell responses.
authors.affiliation: Benaroya Research Institute, Seattle, WA 98101, USA.
authors.forename: Meghan A
authors.initials: MA
authors.lastname: Koch
authors.forename: Kerri R
authors.initials: KR
authors.lastname: Thomas
authors.forename: Nikole R
authors.initials: NR
authors.lastname: Perdue
authors.forename: Kate S
authors.initials: KS
authors.lastname: Smigiel
authors.forename: Shivani
authors.initials: S
authors.lastname: Srivastava
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D000098815:T-bet Transcription Factor
chemical_list: C515188:Cxcr3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053712:Interleukin-12 Receptor beta 2 Subunit; D054367:Receptors, CXCR3; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma