Establishment of tissue-resident self-antigen-specific regulatory T cells protects the lung against recurrent injury 2255936

Abstract Introduction Self-reactive T cells present a threat to normal healthy tissue and are heavily regulated at steady-state by various mechanisms of peripheral tolerance. We previously reported a near-unilateral expansion of CD4+ Foxp3+ regulatory T cells (Tregs) among self-antigen-specific T cell populations during acute autoimmune lung injury which in turn limits further inflammation. Understanding the long-term consequences of this skew towards a Treg phenotype among injury-experienced self-antigen-specific T cells promises new insights into how tolerance is maintained over time and how it may be subverted during the pathogenesis of autoimmunity. Methods We utilized our novel CC10-SmUSA mouse, which expresses a model self-antigen containing multiple CD4+ T cell epitopes in lung tissue, in conjunction with peptide:MHC class II tetramers to directly identify and characterize self-antigen-specific Tregs that have previously expanded in the context of lung injury. Results Following immune-mediated lung injury, the phenotype of lung self-antigen-specific T cells remained stably enriched for Tregs in the secondary lymphoid organs (SLO) and lungs for several months. The frequency of these self-antigen-specific Tregs also remained highly elevated with populations in the lungs being tissue-resident. Upon subsequent challenge with influenza infection, previously injured mice exhibited less weight loss with a more rapid expansion of self-antigen-specific Tregs. Conclusion Our findings suggest that self-antigen-specific Tregs expanded in response to acute lung injury establish residence in the tissue and local draining lymph nodes to promote improved tissue homeostasis and resilience during future insults. Further characterization of these injury-experienced Tregs may help deepen our understanding of how immune memory develops with regard to peripheral tolerance. Funding Source National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID); American Lung Association (ALA) Topic Categories Basic Autoimmunity (BA)