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Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637
How organ-specific central tolerance is established and regulated has been an intriguing question. Lymphotoxin β receptor (LTβR) deficiency is associated with autoimmune phenotypes characterized by humoral and cellular autoreactivity to peripheral organs. Whether this results from defective negative selection of T cells directed at tissue-restricted Ags has not been well understood. By tracing the development of OT-I thymocytes in rat insulin 2 promoter-mOVA transgenic mice on either Ltbr+/+ or Ltbr–/– background, we demonstrate that LTβR is necessary for thymic negative selection. LTβR deficiency resulted in a dramatic escape of "neo-self" specific OT-I cells that persist in circulation and lead to development of peri-insulitis. When the underlying mechanism was further explored, we found interestingly that LTβR deficiency did not result in reduced thymic expression of mOVA. Instead, LTβR was revealed to control the expression of thymic medullary chemokines (secondary lymphoid tissue chemokine (SLC) and EBV-induced molecule 1 ligand chemokine (ELC)) which are required for thymocytes migration and selection in medulla. Furthermore, RIP-mOVA transgenic mice on SLC/ELC deficient background (plt) demonstrated significant impaired negative selection of OT-I cells, suggesting that the dysregulation of SLC/ELC- expression alone in Ltbr–/– thymi can be sufficient to impair thymic negative selection. Thus, LTβR has been revealed to play an important role in thymic negative selection of organ-specific thymocytes through thymic medullary chemokines regulation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by Grants from National Institutes of Health AI062026 and DK58897 (to Y.X.F.).
2 Address correspondence and reprint requests to Dr. Yang-Xin Fu, Department of Pathology and Committee on Immunology, The University of Chicago, 5841 S. Maryland, Room J541, MC3083, Chicago, IL 60637. E-mail address: yfu{at}uchicago.edu
3 Abbreviations used in this paper used in this manuscript: Treg, regulatory T cell; TRA, tissue-restricted self-Ag; SLC, secondary lymphoid tissue chemokine; ELC, EBV-induced molecule 1 ligand chemokine; mTEC, medullary thymic epithelial cell; Aire, autoimmune regulator; LTβR, lymphotoxin β receptor; RIP, rat insulin 2 promoter; WT, wild type; DC, dendritic cell; TRAF6, TNF receptor-associated factor 6; RelB, v-rel reticuloendotheliosis viral oncogenehomolog B; CCR7, chemokine (C-C motif) receptor 7; SP, single positive; DP, double positive.
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