Human LY9 governs CD4 <sup>+</sup> T cell IFN-γ immunity to <i>Mycobacterium tuberculosis</i>
Masato Ogishi, Julia Puchan, Rui Yang, Andrés A. Arias, Ji Eun Han, Tina Nguyen, Rebeca Gutiérrez-Cózar, Clément Conil, Yoann Seeleuthner, Darawan Rinchai, Peng Zhang, Khoren Ponsin, Matthieu Chaldebas, Yi Feng, Anna‐Lena Neehus, Ottavia M. Delmonte, Taushif Khan, Nils Landegren, Daniel Eriksson, Jonathan Bohlen, Jessica N. Peel, Iris Fagniez, Simon J. Pelham, Wei‐Te Lei, Maya Chrabieh, Candice Lainé, Hind Ouair, Ibtihal Benhsaien, A. Abid, Ismail Abderahmani Rhorfi, Hicham Souhi, Hanane El Ouazzani, Rafik Aniss, Sean Riminton, Olle Kämpe, Stuart E. Turvey, Nico Marr, Luigi D. Notarangelo, Nevin Hatipoğlu, Ahmed Aziz Bousfiha, Tayfun Özçelık, Jamila El Baghdadi, Aurélie Cobat, S. Cindy, Laurent Abel, Anne Puel, Jacinta Bustamante, Pablo Engel, Philippe Gros, Stuart G. Tangye, Federica Sallusto, Stéphanie Boisson‐Dupuis, Jean‐Laurent Casanova
Abstract
CD4 + T cells are indispensable for optimal immunity to Mycobacterium tuberculosis ( M.tb ), a pathogen that triggers tuberculosis (TB) in humans. M.tb -specific human CD4 + T cells are known to polarize toward an interferon-γ (IFN-γ)–producing, CCR4 − CCR6 + CXCR3 + T-bet + RORγT + T helper 1* cell (T H 1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10 −5 individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T H 1* cells. T H 1* cells express higher levels of LY9 than other CD4 + T cells. Mechanistically, LY9 polarizes naïve CD4 + T cells toward memory T H 1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory T H 1*, but not T H 1, cells in a T cell–intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. LY9 is likely to govern an optimal T H 1* cell– and IFN-γ–dependent protective immunity to M.tb in humans.