title: Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation.
abstract: Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level proinflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a Foxn1 conditional knockout mouse model that induces accelerated thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype consisting of cellular infiltration into non-lymphoid tissues, increased TNF-α production, and elevated serum IL-6. Autoreactive T cell clones were detected in the periphery of Foxn1 conditional knockout mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related regulatory T cell accumulation in naturally aged mice, but not inflammatory infiltration. Taken together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a contributing source of chronic inflammation (inflammaging).
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107.
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Coder
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107.
authors.forename: Linhui
authors.initials: L
authors.lastname: Ruan
authors.affiliation: Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107 dong-ming.su@unthsc.edu.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Su
mesh_terms: D000367:Age Factors; D000818:Animals; D015551:Autoimmunity; D060833:Cellular Microenvironment; D002908:Chronic Disease; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology; D060966:Clonal Selection, Antigen-Mediated; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics; D055785:Gene Knockdown Techniques; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C090140:Whn protein