IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes

Amanda C. Poholek; Dragana Jankovic; Alejandro V. Villarino; Franziska Petermann; Angela Hettinga; Dror S. Shouval; Scott B. Snapper; Susan M. Kaech; Stephen R. Brooks; Golnaz Vahedi; Alan Sher; Yuka Kanno; John J. O’Shea

doi:10.1126/sciimmunol.aaf8612

Research ArticleAUTOIMMUNITY

IL-10 induces a STAT3-dependent autoregulatory loop in T_H2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes

Amanda C. Poholek¹,²,*,
Dragana Jankovic³,
Alejandro V. Villarino¹,
Franziska Petermann¹,
Angela Hettinga²,
Dror S. Shouval⁴,⁵,
Scott B. Snapper⁴,⁶,
Susan M. Kaech⁷,
Stephen R. Brooks⁸,
Golnaz Vahedi¹,⁹,
Alan Sher³,
Yuka Kanno¹ and
John J. O’Shea¹,*

¹Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.
²Department of Pediatrics and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
³Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁴Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA 02115, USA.
⁵Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁶Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁷Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
⁸Biodata Mining and Discovery Section, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
⁹Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

↵*Corresponding author. Email: poholeka{at}pitt.edu (A.C.P.); john.oshea{at}nih.gov (J.J.O.)

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Science Immunology 11 Nov 2016:
Vol. 1, Issue 5, eaaf8612
DOI: 10.1126/sciimmunol.aaf8612

Amanda C. Poholek

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.Department of Pediatrics and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

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For correspondence: poholeka@pitt.edu john.oshea@nih.gov

Dragana Jankovic

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

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Alejandro V. Villarino

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.

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Franziska Petermann

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.

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Angela Hettinga

Department of Pediatrics and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

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Dror S. Shouval

Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA 02115, USA.Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

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Scott B. Snapper

Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, MA 02115, USA.Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

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Susan M. Kaech

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

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Stephen R. Brooks

Biodata Mining and Discovery Section, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.

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Golnaz Vahedi

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

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Alan Sher

Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

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Yuka Kanno

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.

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John J. O’Shea

Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health, Bethesda, MD 20892, USA.

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For correspondence: poholeka@pitt.edu john.oshea@nih.gov

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Regulating Blimp-1 in T_H2 cells

The transcription factor Blimp-1 has been reported to limit autoimmunity in T cells. Now, Poholek et al. explore the mechanisms regulating Blimp-1 expression in T helper 2 (T_H2) cells. They found that the cytokine interleukin-10 (IL-10) induced Blimp-1 expression in T_H2 cells through STAT3. Signal transducer and activator of transcription 3 (STAT3) and Blimp-1 then acted together to boost IL-10 expression in a positive regulatory loop. The induced Blimp-1 then limited cell expansion by inhibiting STAT5 induction of cell cycle and antiapoptotic genes. Thus, by activating Blimp-1, IL-10 may prevent cell expansion, thus restraining autoimmunity.

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IL-10 induces a STAT3-dependent autoregulatory loop in T_H2 cells that promotes Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes

Regulating Blimp-1 in T_H2 cells

Science Immunology

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