Nature immunology · 2025
Cholinergic regulation of thymocyte negative selection.
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Liu Shaofeng, Zheng Chunxing, Nechanitzky Robert, Luo Ping, Ramachandran Parameswaran, Nguyen Dat, Elia Andrew J, Moghadas Jafari Soode, Law Rhoda, Snow Bryan E, Wakeham Andrew C, Berger Thorsten, Chen Hui, Gill Kyle T, Mcwilliam Ryan, Fortin Jerome, Modares Nastaran Fazel, Saunders Mary E, Murakami Kiichi, Qiu Yangmin, You Zhiwei, Mohtashami Mahmood, Qi Hai, Ohashi Pamela S, Zúñiga-Pflücker Juan Carlos, Mak Tak W
Аннотация
The immune and nervous systems use a common chemical language for communication, namely, the cholinergic signaling involving acetylcholine (ACh) and its receptors (AChRs). Whether and how this language also regulates the development of the immune system is poorly understood. Here, we show that mouse CD4+CD8+ double-positive thymocytes express high levels of α9 nicotinic AChR (nAChR) and that this receptor controls thymic negative selection. α9 nAChR-deficient mice show an altered T cell receptor (TCR) repertoire and reduced CD4+ and CD8+ T cells in a mixed bone marrow chimera setting. α9 nAChR-mediated signaling regulates TCR strength and thymocyte survival. Thymic tuft cells, B cells and some T cells express choline acetyltransferase and are potential ACh sources, with ACh derived from T cells having the most important role. Furthermore, α9 nAChR deficiency during thymocyte development contributes to the altered development of autoimmune diseases in mice. Our results thus reveal a mechanism controlling immune cell development that involves cholinergic signaling.