Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells

Amber Papillion, Michael D. Powell, Danielle A. Chisolm, Holly Bachus, Michael J. Fuller, Amy S. Weinmann, Alejandro Villarino, John J. O'Shea, Beatriz León, Kenneth J. Oestreich, André Ballesteros-Tato

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Sustained T cell receptor (TCR) stimulation is required for maintaining germinal center T follicular helper (GC-TFH) cells. Paradoxically, TCR activation induces interleukin-2 receptor (IL-2R) expression and IL-2 production, thereby initiating a feedback loop of IL-2 signaling that normally inhibits TFH cells. It is unclear how GC-TFH cells can receive prolonged TCR signaling without succumbing to the detrimental effects of IL-2. Using an influenza infection model, we show here that GC-TFH cells secreted large amounts of IL-2 but responded poorly to it. To maintain their IL-2 hyporesponsiveness, GC-TFH cells required intrinsic IL-6 signaling. Mechanistically, we found that IL-6 inhibited up-regulation of IL-2Rβ (CD122) by preventing association of STAT5 with the Il2rb locus, thus allowing GC-TFH cells to receive sustained TCR signaling and produce IL-2 without initiating a TCR/IL-2 inhibitory feedback loop. Collectively, our results identify a regulatory mechanism that controls the generation of GC-TFH cells.

Original languageEnglish (US)
Article numbereaaw7636
JournalScience immunology
Volume4
Issue number39
DOIs
StatePublished - Sep 13 2019
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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