Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration

Becker, Maike; Joseph, Sini S.; Garcia-Carrizo, Francisco; Tom, Robby Z.; Opaleva, Daria; Serr, Isabelle; Tschöp, Matthias H. ; Schulz, Tim J.; Hofmann, Susanna M. und Daniel, Carolin (2023): Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration. In: Cell Metabolism, Vol. 35, No. 10, 1736-1751.e7

Abstract

Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.

• Item Type: Journal article
• Keywords: exercise; voluntary wheel running; tissue Tregs; immune tissue crosstalk; injury; muscle function; IL6Ra signaling; niche-specific Tregs; immunometabolism; immune-metabolic crosstalk
• Faculties: Medicine > Institute for Medical Information Processing, Biometry and Epidemiology; Medicine > Medical Center of the University of Munich > Medical Clinic and Outpatient Clinic IV (Endocrinology, nephrology, other sections)
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1550-4131
• Language: English