Redox status regulates autophagy in thymic stromal cells and promotes T cell tolerance

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-10, Vol.119 (40), p.e2204296119
• Main Authors: Semwal, Manpreet K, Hester, Allison K, Xiao, Yangming, Udeaja, Chioma, Cepeda, Sergio, Verschelde, 2nd, John S, Jones, Nicholas, Wedemeyer, Sarah A, Emtage, Simon, Wimberly, Kymberly, Griffith, Ann V
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Antigen presentation; Antigens; Autoantigens; Autophagy; Autophagy - genetics; Autophagy - immunology; Beclin-1 - genetics; Biological Sciences; Catalase; Catalase - genetics; Clonal deletion; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Immune Tolerance; Immunological tolerance; Intracellular Signaling Peptides and Proteins - genetics; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; Oxidation-Reduction; Stromal cells; Stromal Cells - immunology; Thymus; Thymus Gland - cytology; Thymus Gland - immunology; Transgenic mice
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2204296119

Thymic stromal cells (TSCs) are critical regulators of T cell tolerance, but their basic biology has remained under-characterized because they are relatively rare and difficult to isolate. Recent work has revealed that constitutive autophagy in TSCs is required for self-antigen presentation and central T cell tolerance induction; however, the mechanisms regulating constitutive autophagy in TSCs are not well understood. Hydrogen peroxide has been shown to increase autophagy flux in other tissues, and we previously identified conspicuously low expression of the hydrogen peroxide-quenching enzyme catalase in TSCs. We investigated whether the redox status of TSCs established by low catalase expression regulates their basal autophagy levels and their capacity to impose central T cell tolerance. Transgenic overexpression of catalase diminished autophagy in TSCs and impaired thymocyte clonal deletion, concomitant with increased frequencies of spontaneous lymphocytic infiltrates in lung and liver and of serum antinuclear antigen reactivity. Effects on clonal deletion and autoimmune indicators were diminished in catalase transgenic mice when autophagy was rescued by expression of the Becn1 knock-in allele. These results suggest a metabolic mechanism by which the redox status of TSCs may regulate central T cell tolerance.