Human LY9 governs CD4 <sup>+</sup> T cell IFN-γ immunity to <i>Mycobacterium tuberculosis</i>

CD4<sup>+</sup> T cells are indispensable for optimal immunity to <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>), a pathogen that triggers tuberculosis (TB) in humans. <i>M.tb</i>-specific human CD4<sup>+</sup> T cells are known to polarize toward an interferon-γ (IFN-γ)-producing, CCR4<sup>-</sup>CCR6<sup>+</sup>CXCR3<sup>+</sup>T-bet<sup>+</sup>RORγT<sup>+</sup> T helper 1* cell (T<sub>H</sub>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<sup>-5</sup> individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T<sub>H</sub>1* cells. T<sub>H</sub>1* cells express higher levels of LY9 than other CD4<sup>+</sup> T cells. Mechanistically, LY9 polarizes naïve CD4<sup>+</sup> T cells toward memory T<sub>H</sub>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<sub>H</sub>1*, but not T<sub>H</sub>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<sub>H</sub>1* cell- and IFN-γ-dependent protective immunity to <i>M.tb</i> in humans.

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Journal
Science Immunology
Published
2025-05-30
DOI
https://doi.org/10.1126/sciimmunol.ads7377
Citations
7
Primary Topic
Immune Cell Function and Interaction
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article
Field-Weighted Citation Impact
5.58
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article

Human LY9 governs CD4 + T cell IFN-γ immunity to Mycobacterium tuberculosis

Simon J. Pelham, Ismail Abderahmani Rhorfi, Andrés A. Arias, Wei‐Te Lei et al.
7 citations
Science Immunology
Immune Cell Function and Interaction
5.58
article

Human LY9 governs CD4 + T cell IFN-γ immunity to Mycobacterium tuberculosis

Simon J. Pelham, Ismail Abderahmani Rhorfi, Andrés A. Arias, Wei‐Te Lei, Jessica N. Peel, Tayfun Özçelık, Darawan Rinchai, Luigi Daniele Notarangelo, Tina Nguyen, Ottavia M. Delmonte, Yoann Seeleuthner, Aurélie Cobat, Nils Landegren, Matthieu Chaldebas, Hind Ouair, Stuart E. Turvey, Candice Lainé, Philippe Gros, Federica Sallusto, Jean‐Laurent Casanova, Ji Eun Han, S. Cindy, Nevin Hatipoğlu, Ahmed Aziz Bousfiha, Nico Marr, Anne Puel, Hicham Souhi, Daniel Eriksson, Anna‐Lena Neehus, Jamila El Baghdadi, Sean Riminton, Pablo Engel, Ibtihal Benhsaien, Jonathan Bohlen, Taushif Khan, Maya Chrabieh, Stuart G. Tangye, Jacinta Bustamante, Olle Kämpe, Julia Puchan, Masato Ogishi, Rebeca Gutiérrez-Cózar, Stéphanie Boisson‐Dupuis, Clément Conil, Laurent Abel, Khoren Ponsin, Peng Zhang, A. Abid, Yi Feng, Rui Yang, Hanane El Ouazzani, Iris Fagniez, Rafik Aniss
article en
7 citations

Abstract

CD4<sup>+</sup> T cells are indispensable for optimal immunity to <i>Mycobacterium tuberculosis</i> (<i>M.tb</i>), a pathogen that triggers tuberculosis (TB) in humans. <i>M.tb</i>-specific human CD4<sup>+</sup> T cells are known to polarize toward an interferon-γ (IFN-γ)-producing, CCR4<sup>-</sup>CCR6<sup>+</sup>CXCR3<sup>+</sup>T-bet<sup>+</sup>RORγT<sup>+</sup> T helper 1* cell (T<sub>H</sub>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<sup>-5</sup> individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T<sub>H</sub>1* cells. T<sub>H</sub>1* cells express higher levels of LY9 than other CD4<sup>+</sup> T cells. Mechanistically, LY9 polarizes naïve CD4<sup>+</sup> T cells toward memory T<sub>H</sub>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<sub>H</sub>1*, but not T<sub>H</sub>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<sub>H</sub>1* cell- and IFN-γ-dependent protective immunity to <i>M.tb</i> in humans.

Science ImmunologyVol. 10(107)
Uppsala University (SE), Mohammed V University (MA), The University of Sydney (AU), National Institutes of Health (US), Qatar Airways (Qatar) (QA), Karolinska University Hospital (SE), Howard Hughes Medical Institute (US), Garvan Institute of Medical Research (AU), Inserm (FR), Bilkent University (TR), Université Paris Cité (FR), Royal Australasian College of Physicians (AU), Science for Life Laboratory (SE), Concord Repatriation General Hospital (AU), Military Hospital (PK), Karolinska Institutet (SE), UNSW Sydney (AU), ETH Zurich (CH), Universidad de Antioquia (CO), Bakırköy Dr.Sadi Konuk Eğitim ve Araştırma Hastanesi (TR), Sağlık Bilimleri Üniversitesi (TR), Sidra Medical and Research Center (QA), National Institute of Allergy and Infectious Diseases (US), Centre Hospitalier Universitaire Ibn Rochd (MA), Hamad bin Khalifa University (QA), BC Children's Hospital (CA), Institut des Maladies Génétiques Imagine (FR), McGill University (CA), Università della Svizzera italiana (CH), Universitat de Barcelona (ES), Rockefeller University (US), University of Hassan II Casablanca (MA)
Good health and well-being
Openalex Percentile: Top 4%
Immune Cell Function and Interaction
5.58
DOIOpen Access PDFOpenAlex
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