MOG-specific Treg generation is potentially affected by thymic atrophy

Abstract

Purpose: Increased chronic inflammation in the elderly is partially attributed to the disruption of central immune tolerance, comprising thymocyte negative selection and regulatory T cell (Treg) generation due to age-related thymic atrophy. Mechanistically, decreased self-antigen expression by thymic epithelial cells (TECs) in the atrophied thymus is unable to induce strong T cell receptor (TCR) signaling so that thymocyte negative selection is defective and polyclonal Treg generation is relatively enhanced. However, it was reported that certain specific clonal Treg generation is defective. Given the fact that aging aggravates relapsing-remitting multiple sclerosis (mouse model experimental autoimmune encephalomyelitis, EAE) and myelin oligodendrocyte glycoprotein (MOG) specific Treg is a key to resolve EAE, we ask whether the generation of monoclonal MOG-specific Treg cells are defective during thymic atrophy. Methods: We used inducible thymic atrophy mice reconstituted with MOG-specific TCR transgenic bone marrow to investigate the alteration of generation and function of MOG-specific Treg cells. Results: We found that the mog gene expression in TECs is decreased in the atrophied thymus, implying a potential contributor to the alteration of MOG-specific T cell development. At the peak stage of EAE, the ratio of MOG-specific Treg cells to MOG-specific conventional T cells in the central nervous system of thymic atrophy mice is decreased, with a decreased trend of Foxp3 expression in these Treg cells. Although we did not find obvious clinical differences in EAE between the thymic atrophy and normal thymus groups at the small sample numbers, we will continue to investigate the clinical and pathological differences via increasing animal numbers. Conclusion: This study suggests that even though in the aged thymus the generation of polyclonal Treg cells is enhanced, certain tissue-specific Treg cell generation could be reduced, leaving holes in the Treg-TCR repertoire.