Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development.

Huishan Tao,Nan-Shih Liao,Shirley Luckhart,John W Sleasman,Lei Li,Xiao-Ping Zhong,Kimberly S Schluns

doi:10.3389/fimmu.2021.623280

Abstract

Expression of tissue-restricted antigens (TRAs) in thymic epithelial cells (TECs) ensures negative selection of highly self-reactive T cells to establish central tolerance. Whether some of these TRAs could exert their canonical biological functions to shape thymic environment to regulate T cell development is unclear. Analyses of publicly available databases have revealed expression of transcripts at various levels of many cytokines and cytokine receptors such as IL-15, IL-15Rα, IL-13, and IL-23a in both human and mouse TECs. Ablation of either IL-15 or IL-15Rα in TECs selectively impairs type 1 innate like T cell, such as iNKT1 and γδT1 cell, development in the thymus, indicating that TECs not only serve as an important source of IL-15 but also trans-present IL-15 to ensure type 1 innate like T cell development. Because type 1 innate like T cells are proinflammatory, our data suggest the possibility that TEC may intrinsically control thymic inflammatory innate like T cells to influence thymic environment.

Highlights

Two lineages of T cells, the αβT cell and γδT cell lineages that express distinct TCR receptor αβ chains and γδ chains, are generated in the thymus. αβT cells develop sequentially from the CD4−CD8− double negative (DN) stage, the CD4+CD8+ double positive (DP) stage, and to the TCRαβ+CD4+CD8− or TCRαβ+CD4−CD8+ single positive (SP) stage
While multiple previous studies have found radioresistant cell derived IL-15 and/or IL-15Rα or have suggested that medullary TECs (mTECs)-derived IL-15 and/or IL-15Rα are important for invariant natural killer T (iNKT) cell, especially iNKT1 cell, development, no thymic epithelial cells (TECs)-specific ablation of these molecules have been reported [6, 7, 62]
We found that ablation of either IL-15 or IL-15Rα in TECs causes significant impairment of iNKT1 and γδT1 cell development in the thymus

Summary

Introduction

Two lineages of T cells, the αβT cell and γδT cell lineages that express distinct TCR receptor αβ chains and γδ chains, are generated in the thymus. αβT cells develop sequentially from the CD4−CD8− double negative (DN) stage, the CD4+CD8+ double positive (DP) stage, and to the TCRαβ+CD4+CD8− or TCRαβ+CD4−CD8+ single positive (SP) stage. In contrast to conventional αβT cells, iNKT cells, MAIT cells, and γδT cells can complete their differentiation into effector cells in the thymus, which appears to be regulated by thymic environment [6,7,8,9,10,11]. These effector lineages include the type 1 sublineage (iNKT1/MAIT1/γδT1) that express T-bet and IFNγ, the type 2 sublineage (iNKT2/MAIT2/γδT2) that express Gata and IL-4, and the type 3 sublineage (iNKT17/MAIT17/γδT17) that express RORγt and IL-17A [8, 9, 12,13,14,15,16,17,18,19]. While naïve T cells require several days to differentiate to effector cells, these innate like T cells can be activated quickly and are able to rapidly produce a variety of cytokines in response to agonistic stimuli to shape both innate and adaptive immunity

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Conclusion