Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation

 Significance Statement

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.

 Thymic Involution Perturbs Negative Selection Leading Autoreactive T Cells Induce Chronic Inflammation. Global Medical Discovery

Journal Reference

J Immunol. 2015;194(12):5825-37.

Coder BD1, Wang H1, Ruan L1, Su DM2.

[expand title=”Show Affiliations”]
  1. Department of Cell Biology and Immunology, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107.
  2. 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).

Copyright © 2015 by The American Association of Immunologists, Inc.

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