Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery.
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.
Barnes
Michael J
MJ
Department of Genetics, The Scripps Research Institute, La Jolla, CA, USA. mbarnes@scripps.edu
Krebs
Philippe
P
Harris
Nathaniel
N
Eidenschenk
Celine
C
Gonzalez-Quintial
Rosana
R
Arnold
Carrie N
CN
Crozat
Karine
K
Sovath
Sosathya
S
Moresco
Eva Marie
EM
Theofilopoulos
Argyrios N
AN
Beutler
Bruce
B
Hoebe
Kasper
K
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
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