Age-related thymic involution results in decreased output of naïve T cells which reduces the T cell receptor repertoire diversity, thereby leading to immunosenescence. Moreover, thymic involution via the increased release of autoreactive T cells result in inflammaging (a term describing chronic inflammatory state, associated with the aging process). The authors proposed targeting thymic involution would be a promising strategy for modulating chronic inflammation.
J Immunol. 2015;194(12):5825-37.
Coder BD1, Wang H1, Ruan L1, Su DM2.[expand title=”Show Affiliations”]
- Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107.
- Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107 [email protected]
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).
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