MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt⁺ T cells.

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Abstract

Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (T(H)17) cells and regulatory T cells (T(regs)) in the intestine. Here, we report that microbiota-induced T(regs) express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to T(H)17 cells. In the absence of RORγt(+) T(regs), T(H)2-driven defense against helminths is more efficient, whereas T(H)2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of type 3 RORγt(+) T(regs) and T(H)17 cells and acts as a key factor in balancing immune responses at mucosal surfaces.

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Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

M. J. Barnden, J. Allison, W R Heath … (1998)

We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.

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IL-17 family cytokines and the expanding diversity of effector T cell lineages.

Casey T. Weaver, Robin Hatton, Paul R Mangan … (2007)

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.

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Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.

Ye Zheng, Ashutosh Chaudhry, Arnold Kas … (2009)

In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.

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Journal

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

ISSN (Electronic): 1095-9203

ISSN (Print): 0036-8075

Publication date (Electronic): Aug 28 2015

Volume: 349

Issue: 6251

Affiliations

[1 ] Institut Pasteur, Microenvironment and Immunity Unit, 75724 Paris, France.

[2 ] Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.

[3 ] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama, Kanagawa 230-0045, Japan. PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan.

[4 ] The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

[5 ] INSERM, U1163, Laboratory of Intestinal Immunity, Paris, France. Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, Paris, France. INRA Micalis UMR1319, Jouy-en-Josas, France.

[6 ] Center of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Zentrum München, Munich, Germany.

[7 ] Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.

[8 ] INSERM, U1163, Laboratory of Intestinal Immunity, Paris, France. Université Paris Descartes-Sorbonne Paris Cité and Institut Imagine, Paris, France.

[9 ] Institut Pasteur, Biology and Genetics of Bacterial Cell Wall, 75724 Paris, France. INSERM, Groupe Avenir, 75015 Paris, France.

[10 ] Department of Infection Biology at the Institute of Clinical Microbiology, Immunology and Hygiene, University Clinic Erlangen and Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.

[11 ] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama, Kanagawa 230-0045, Japan. CREST, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.

[12 ] Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan. Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.

[13 ] Institut Pasteur, Microenvironment and Immunity Unit, 75724 Paris, France. gerard.eberl@pasteur.fr.

Article

Publisher Item ID: science.aac4263

DOI: 10.1126/science.aac4263

PubMed ID: 26160380

SO-VID: 8e0906d2-b812-4f6c-acd0-866f9ee498c8

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MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt⁺ T cells.

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Gamma Delta T cells

Most cited references 24

Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

IL-17 family cytokines and the expanding diversity of effector T cell lineages.

Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses.

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Cited by 363

Most referenced authors 1,501