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Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity

Nature Immunology volume 14, pages 271–280 (2013)Cite this article

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Abstract

The gut mucosa hosts large numbers of activated lymphocytes that are exposed to stimuli from the diet, microbiota and pathogens. Although CD4+ T cells are crucial for defense, intestinal homeostasis precludes exaggerated responses to luminal contents, whether they are harmful or not. We investigated mechanisms used by CD4+ T cells to avoid excessive activation in the intestine. Using genetic tools to label and interfere with T cell–development transcription factors, we found that CD4+ T cells acquired the CD8-lineage transcription factor Runx3 and lost the CD4-lineage transcription factor ThPOK and their differentiation into the TH17 subset of helper T cells and colitogenic potential, in a manner dependent on transforming growth factor-β (TGF-β) and retinoic acid. Our results demonstrate considerable plasticity in the CD4+ T cell lineage that allows chronic exposure to luminal antigens without pathological inflammation.

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Figure 1: Reciprocal regulation of ThPOK and Runx3 in intestinal tissue.
Figure 2: TGF-β and RA concomitantly induce Treg cells and ThPOKloRunx3hiCD4+ T cells.
Figure 3: Signaling by TGF-β and RA in intestinal CD4+ T cells is required for downmodulation of ThPOK expression and for CD8α expression in vivo.
Figure 4: Loss of ThPOK by activated CD4+ T cells hinders the development of colitis.
Figure 5: Continuous ThPOK expression is required for the inflammatory activity of CD4+ T cells.
Figure 6: Upregulation of Runx3 expression precedes the downmodulation of ThPOK expression and the expression of CD8αα by intestinal CD4+ T cells.
Figure 7: Runx3 expression by CD4+ T cells inversely correlates with their inflammatory potential.
Figure 8: Enhanced resistance of Cd4(ΔRunx3) mice to infection with C. rodentium.

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Change history

  • 28 January 2013

    In the version of this article initially published online, the black and red labels in Figure 2c were incorrect. The correct labels are "CD4+ (–)" (black label) and "CD4+CD8αα+ + TGF-β" (red label). The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank K. Velinzon and Y. Shatalina for sorting cells; members of the Nussenzweig, Steinman, Marraffini and Tavazoie laboratories and employees of the The Rockefeller University for assistance; R. Noelle (Dartmouth University) for dnRaralsl/lsl mice; D. Littman (New York University) for Runx3-YFP mice; L. Glimcher (Cornell University) for Tbx21 vectors; and L. Marraffini, S. Tavazoie, G. Kim, M. Kronenberg, H. Cheroutre and members of the Mucida laboratory, particularly L. Feighery, for discussions and critical reading and editing of the manuscript. Supported by the Ellison Medical Foundation (D.M.), the Irma T. Hirschl Trust (D.M.), the Crohn's & Colitis Foundation of America (D.M.), the US National Institutes of Health (R01 DK093674-01 to D.M.), the Leona M. and Harry B. Helmsley Charitable Trust (D.M.), Fundação de Amparo à Pesquisa do Estado de São Paulo (F.A.C.-P.) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (F.A.C.-P.).

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Authors and Affiliations

  1. Laboratory of Mucosal Immunology, The Rockefeller University, New York, New York, USA

    Bernardo Sgarbi Reis, Aneta Rogoz, Frederico Azevedo Costa-Pinto & Daniel Mucida

  2. Department of Pathology, School of Veterinary Medicine, University of Sao Paulo, Sao Paulo, Brazil

    Frederico Azevedo Costa-Pinto

  3. Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan

    Ichiro Taniuchi

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  1. Bernardo Sgarbi Reis
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Contributions

D.M. conceived of and supervised this study and wrote the paper; B.S.R. and D.M. designed experiments; B.S.R., A.R. and D.M. did experiments; B.S.R. prepared figures and helped with manuscript preparation; F.A.C.-P. analyzed and assigned scores to intestinal tissue for inflammation and helped with manuscript preparation; and I.T. provided mouse strains and constructs for overexpression of genes and helped with manuscript preparation.

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Correspondence to Daniel Mucida.

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Reis, B., Rogoz, A., Costa-Pinto, F. et al. Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity. Nat Immunol 14, 271–280 (2013). https://doi.org/10.1038/ni.2518

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