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That Induce Chronic Inflammation Selection Leading to Autoreactive T Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation This information is current as Brandon D. Coder, Hongjun Wang, Linhui Ruan and of October 3, 2021. Dong-Ming Su J Immunol 2015; 194:5825-5837; Prepublished online 8 May 2015; doi: 10.4049/jimmunol.1500082 http://www.jimmunol.org/content/194/12/5825 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/05/08/jimmunol.150008 Material 2.DCSupplemental http://www.jimmunol.org/ References This article cites 69 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/194/12/5825.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 3, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation Brandon D. Coder, Hongjun Wang,1 Linhui Ruan,2 and Dong-Ming Su 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 accel- erated 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-a 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 Downloaded from 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). The Journal of Immunology, 2015, 194: 5825–5837. hronic inflammation is a ubiquitous feature of the aging cancers including colitis-associated colon cancer and hepatocellular http://www.jimmunol.org/ process and implicated in virtually every age-related carcinoma (5). IL-6 and TNF-a are the most predictive inflamma- C disease (1, 2). The term “inflammaging” describes the tory biomarkers and are highly correlated with “all-cause” mor- low-level, chronic, and systemic proinflammatory state that bidity and mortality in the elderly (6). Although the etiology accompanies advanced age in the absence of infection (1). Even of inflammaging is not fully understood, the source of proin- though clinical manifestations are not obvious, the presence flammatory factors is primarily attributed to the combination of proinflammatory factors such as IL-6, TNF-a,IL-1,and of cellular senescence–induced senescence-associated secretory C-reactive protein are associated with the severity, incidence, and phenotype (SASP) and the persistent activation of immune cells mortality of cardiovascular diseases such as atherosclerosis (1, 2, 7). by guest on October 3, 2021 and myocardial infarction (3), neurodegenerative diseases such as The persistent activation of immune cells is hypothesized to Parkinson’s disease (4) and Alzheimer’s disease (1), and late-life result from chronic cell death and self-debris serving as damage- associated molecular patterns, leading to innate immune cell activation (1, 8) or repeated life-long exposure to latent viral Department of Cell Biology and Immunology, University of North Texas Health infections, such as CMV (9, 10), continuously activating both Science Center at Fort Worth, Fort Worth, TX 76107 innate and adaptive immune responses. However, it is not known 1Current address: Department of Histology and Embryology, Jilin Medical College, Jilin, People’s Republic of China. whether thymic involution can lead to the persistent activation of 2Current address: First Affiliated Hospital, Wenzhou Medical University, Wenzhou, T cells that are capable of inducing inflammaging. People’s Republic of China. The thymus is a primary lymphoid organ comprised of cortical Received for publication January 13, 2015. Accepted for publication April 14, 2015. and medullary thymic epithelial cells (cTECs and mTECs) re- This work was supported by National Institute of Allergy and Infectious Diseases/ sponsible for the development of thymocytes and the generation National Institutes of Health Grants R01AI081995 (to D.-M.S.) and 3R01AI081995- of central immune tolerance toward self-tissues. Thymic-driven 03S1 (to B.D.C.). central immune tolerance is accomplished through two mecha- D.-M.S. and B.D.C. conceived and designed the experiments; B.D.C., L.R., and nisms: the elimination of autoreactive T cell clones via the process H.W. performed the experiments and analyzed the data; and D.-M.S. and B.D.C. wrote the paper. of negative selection (11), and the generation of natural regulatory Address correspondence and reprint requests to Dr. Dong-Ming Su, Department of T cells (nTregs) via diverted differentiation (12, 13). These two Cell Biology and Immunology, University of North Texas Health Center at Fort processes depend on the TCR–self-peptide–MHC avidity and Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107. E-mail address: signal strength, where a weak signal leads to thymocyte survival [email protected] (14), a strong signal leads to clonal deletion (15), and a moderate The online version of this article contains supplemental material. signal plus cytokines (IL-2) leads to nTreg differentiation (16, 17). Abbreviations used in this article: Aire, autoimmune regulator gene; cKO, condi- The efficiencies of negative selection and the differentiation of tional knockout; cTEC, cortical thymic epithelial cell; Ctr, control; DP, double- positive; F-cKO, Foxn1 conditional knockout; fx, loxP-floxed Foxn1 (Foxn1 flox); nTregs are dependent on the production and presentation of tissue- IRBP, interstitial retinol-binding protein; mOVA, membrane-bound ovalbumin; specific Ags on MHC, which is, in part, regulated by the auto- mTEC, medullary thymic epithelial cell; nTreg, natural regulatory T cell; RTE, recent thymic emigrant; SASP, senescence-associated secretory phenotype; SP, immune regulator gene (Aire) in mTECs (18–22). single-positive; TEC, thymic epithelial cell; Teff, T effector cell; Tg, transgenic; The thymus undergoes a progressive and age-related involution T TM, tamoxifen; Treg, regulatory T cell; uCreER , ubiquitous promoter-driven Cre- attributed to the deterioration of the thymic microenvironment (23), recombinase and estrogen-receptor fusion protein; WT, wild-type. which is made of an integrated three-dimensional meshwork of Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 cTECs and mTECs, where TEC differentiation is regulated by the www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500082 5826 INFLAMMAGING RELATED TO THYMIC INVOLUTION Foxn1 gene (24). It has been reported that defects in mTEC as well as sera) of recipient RAG2/2 mice were collected for analysis of structure and the loss of Aire can affect the maintenance of central inflammatory cell infiltration. immune tolerance (25–27) by leading to the generation of fewer Thymic lobe kidney capsule transplantation (28) or deficient nTregs (29), and thereby increasing the incidence of autoimmune disease. However, the mechanisms through which The surgical operation of the kidney capsule transplantation was performed as previously described (31). Intact newborn mouse thymic lobes of fx/fx- thymic involution impacts the two mechanisms of central toler- uCreERT and fx/fx-only with and without mOVA-Tg were directly trans- ance (negative selection and nTregs) are not fully understood. planted into young host OT-II+ TCR-Tg mice. Three days after the graft, Furthermore, whether thymic atrophy alone leads to the release of the host mice were i.p. injected with TM (1 mg/10 g body weight/d) for 3 autoreactive T cells that become persistently activated immune consecutive days to induce deletion of the Foxn1 gene. Two weeks after the last TM injection, the grafted thymi were isolated for FACS analysis of cells and contribute to inflammaging remains
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