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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Blimp-1 expression in T cells extinguishes the fate of T follicular helper cells, drives terminal differentiation, and limits autoimmunity. Although various factors have been described to control Blimp-1 expression in T cells, little is known about what regulates Blimp-1 expression in T helper 2 (TH2) cells and the molecular basis of its actions. We report that signal transducer and activator of transcription 3 (STAT3) unexpectedly played a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Together, Blimp-1 and STAT3 amplified IL-10 production in TH2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and antiapoptotic genes to limit cell expansion. These data elucidate the signals required for Blimp-1 expression in TH2 cells and reveal an unexpected mechanism of action of IL-10 in T cells, providing insights into the molecular underpinning by which Blimp-1 constrains T cell expansion to limit autoimmunity.

Original languageEnglish
Article numbereaaf8612
JournalScience immunology
Volume1
Issue number5
DOIs
StatePublished - 2016
Externally publishedYes

Funding

FundersFunder number
National Institutes of Health
National Institute of General Medical Sciences
National Institute of Allergy and Infectious DiseasesZIAAI001044
National Institute of Arthritis and Musculoskeletal and Skin DiseasesZIAAR041159

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