THEMIS promotes T cell development and maintenance by rising the signaling threshold of the inhibitory receptor BTLA

• 成果类型: Article
• 署名作者: Melique, Suzanne; Vadel, Aurelie; Rouquie, Nelly; Yang, Cui; Bories, Cyrielle; Cotineau, Coline; Saoudi, Abdelhadi; Fazilleau, Nicolas; Lesourne, Renaud
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Toulouse; Universite Toulouse III - Paul Sabatier
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9793
• DOI: 10.1073/pnas.2318773121
• 发表日期: 2024-05-14
• 关键词: protein-tyrosine phosphatases; herpesvirus entry mediator; positive selection; b-lymphocyte; tcr; homeostasis; light; hvem; shp-1; mechanisms

摘要

The current paradigm about the function of T cell immune checkpoints is that these receptors switch on inhibitory signals upon cognate ligand interaction. We here revisit this simple switch model and provide evidence that the T cell lineage protein THEMIS enhances the signaling threshold at which the immune checkpoint BTLA (B - and T - lymphocyte attenuator) represses T cell responses. THEMIS is recruited to the cytoplasmic domain of BTLA and blocks its signaling capacity by promoting/ stabilizing the oxidation of the catalytic cysteine of the tyrosine phosphatase SHP - 1. In contrast, THEMIS has no detectable effect on signaling pathways regulated by PD - 1 (Programmed cell death protein 1), which depend mainly on the tyrosine phosphatase SHP - 2. BTLA inhibitory signaling is tuned according to the THEMIS expression level, making CD8+ T cells more resistant to BTLA - mediated inhibition than CD4+ T cells. In the absence of THEMIS, the signaling capacity of BTLA is exacerbated, which results in the attenuation of signals driven by the T cell antigen receptor and by receptors for IL - 2 and IL - 15, consequently hampering thymocyte positive selection and peripheral CD8+ T cell maintenance. By characterizing the pivotal role of THEMIS in restricting the transmission of BTLA signals, our study suggests that immune checkpoint operability is conditioned by intracellular signal attenuators.