Commitment to the regulatory t cell lineage requires CARMA1 in the thymus but not in the periphery

Michael J. Barnes, Philippe Krebs, Nathaniel Harris, Celine Eidenschenk, Rosana Gonzalez-Quintial, Carrie N. Arnold, Karine Crozat, Sosathya Sovath, Eva Marie Moresco, Argyrios N. Theofilopoulos, Bruce Beutler, Kasper Hoebe

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Regulatory T (Treg) 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+ Treg cells and demonstrate a cell-intrinsic requirement for CARMA1 in thymic Foxp3 induction. However, peripheral Carma1-deficient Treg cells could be generated and expanded in vitro in response to the cytokines transforming growth factor beta (TGFβ) 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 Treg cells are a dynamic population that may expand to limit immunopathology or promote chronic infection. Copyright:

Original languageEnglish (US)
Pages (from-to)513-524
Number of pages12
JournalPLoS biology
Volume7
Issue number3
DOIs
StatePublished - Mar 2009

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Barnes, M. J., Krebs, P., Harris, N., Eidenschenk, C., Gonzalez-Quintial, R., Arnold, C. N., Crozat, K., Sovath, S., Moresco, E. M., Theofilopoulos, A. N., Beutler, B., & Hoebe, K. (2009). Commitment to the regulatory t cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS biology, 7(3), 513-524. https://doi.org/10.1371/journal.pbio.1000051