title: Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery.
abstract: Regulatory T (T(reg)) cells expressing forkhead box P3 (Foxp3) arise during thymic selection among thymocytes with modestly self-reactive T cell receptors. In vitro studies suggest Foxp3 can also be induced among peripheral CD4(+) T cells in a cytokine dependent manner. T(reg) cells of thymic or peripheral origin may serve different functions in vivo, but both populations are phenotypically indistinguishable in wild-type mice. Here we show that mice with a Carma1 point mutation lack thymic CD4(+)Foxp3(+) T(reg) cells and demonstrate a cell-intrinsic requirement for CARMA1 in thymic Foxp3 induction. However, peripheral Carma1-deficient T(reg) cells could be generated and expanded in vitro in response to the cytokines transforming growth factor beta (TGFbeta) and interleukin-2 (IL-2). In vivo, a small peripheral T(reg) pool existed that was enriched at mucosal sites and could expand systemically after infection with mouse cytomegalovirus (MCMV). Our data provide genetic evidence for two distinct mechanisms controlling regulatory T cell lineage commitment. Furthermore, we show that peripheral T(reg) cells are a dynamic population that may expand to limit immunopathology or promote chronic infection.
authors.affiliation: Department of Genetics, The Scripps Research Institute, La Jolla, CA, USA. mbarnes@scripps.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Barnes
authors.forename: Philippe
authors.initials: P
authors.lastname: Krebs
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Harris
authors.forename: Celine
authors.initials: C
authors.lastname: Eidenschenk
authors.forename: Rosana
authors.initials: R
authors.lastname: Gonzalez-Quintial
authors.forename: Carrie N
authors.initials: CN
authors.lastname: Arnold
authors.forename: Karine
authors.initials: K
authors.lastname: Crozat
authors.forename: Sosathya
authors.initials: S
authors.lastname: Sovath
authors.forename: Eva Marie
authors.initials: EM
authors.lastname: Moresco
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology*; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000235:genetics; D051379:Mice; D017354:Point Mutation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D016207:Cytokines; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta