Human LY9 governs CD4+ T-cell IFN-γ immunity to Mycobacterium tuberculosis
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ABSTRACT:
PROVIDER: PRJNA1186189 | ENA |
REPOSITORIES: ENA
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Project description:CD4+ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a virulent pathogen that triggers tuberculosis (TB), in humans, as evidenced by studies of patients with CD4+ T lymphocytopenia. M.tb-specific human CD4+ T cells are known to polarize toward an IFN-γ-producing, T-bet+RORγT+ TH1* memory phenotype. We report that inherited deficiency of the human lymphocytic surface receptor LY9 (SLAMF3, CD229) underlies TB, but not BCG disease, due to dysfunction of TH1* cells. We find autosomal recessive, complete LY9 deficiency in three unrelated patients with TB and one asymptomatic relative, but not in patients with other infections studied, including patients with BCG disease, and in less than 10-5 individuals in the general population. TH1* cells in LY9-deficient individuals show selective impairment in IFN-γ production. By contrast, LY9 deficiency does not disrupt the development or function of leukocyte subsets other than TH1* cells, including TH1 cells. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via SAP, and RORγT without SAP. Among CD4+ T cell subsets, TH1* cells express LY9 at the highest level. Finally, LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1*, but not TH1, cells in a T-cell-intrinsic manner via NFAT1 and RORγT. Human LY9 is thus required for an optimal TH1*-cell- and IFN-γ-dependent protective immunity to M.tb. These findings, in turn, suggest that, without fully functional TH1* cells, TH1 cells and other T cell subsets may not be sufficient for optimal protective immunity to M.tb in humans.
2025-07-16 | GSE281929 | GEO
Project description:Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria
| PRJNA839087 | ENA
Project description:Human IRF1 governs phagocytic IFN-gamma immunity to mycobacteria
| PRJNA901963 | ENA
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, whereas inborn errors of IFN-/ immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-/ immunity. The IRF1-dependent cellular responses to IFN-γ are, both quantitatively and qualitatively, much greater than those to IFN-/ in vitro. Monocyte- and iPSC-derived macrophages from the two patients show no upregulation of at least 20% of the target genes normally induced by IFN-γ. By contrast, cell-intrinsic IFN-/ immunity to diverse viruses, including SARS-CoV-2, is intact. Human IRF1 is, thus, largely redundant for antiviral IFN-/ immunity. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in myeloid cells.
2023-01-12 | GSE218033 | GEO
Project description:Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.
2023-05-12 | GSE203220 | GEO
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, while inborn errors of IFN-a/b immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. They have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2 that is life-threatening in individuals with deficient IFN-a/b. There is a much greater IRF1-dependent response to IFN-γ than IFN-a/b in vitro, both quantitatively and qualitatively. Monocyte-derived macrophages and iPSC-derived macrophages of both patients do not upregulate at least 40% of target genes normally induced by IFN-γ. In contrast, cell-intrinsic IFN-a/b immunity to a wide range of viruses, including HIV and SARS-CoV-2, is maintained. Human IRF1 is thus largely redundant for antiviral IFN-a/b immunity across cell types. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in mononuclear myeloid cells.
2023-01-12 | GSE216488 | GEO
Project description:Inborn errors of human IFN-γ immunity underlie mycobacterial diseases, while inborn errors of IFN-a/b immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe two unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria. They have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2 that is life-threatening in individuals with deficient IFN-a/b. There is a much greater IRF1-dependent response to IFN-γ than IFN-a/b in vitro, both quantitatively and qualitatively. Monocyte-derived macrophages and iPSC-derived macrophages of both patients do not upregulate at least 40% of target genes normally induced by IFN-γ. In contrast, cell-intrinsic IFN-a/b immunity to a wide range of viruses, including HIV and SARS-CoV-2, is maintained. Human IRF1 is thus largely redundant for antiviral IFN-a/b immunity across cell types. By contrast, human IRF1 is essential for IFN-γ immunity to mycobacteria in mononuclear myeloid cells.
2023-01-12 | GSE216486 | GEO
Project description:Human IRF1 governs phagocytic IFN-γ immunity to mycobacteria but not cell-intrinsic IFN-a/b immunity to viruses
| PRJNA893689 | ENA
Project description:Human IRF1 governs phagocytic IFN-γ immunity to mycobacteria but not cell-intrinsic IFN-a/b immunity to viruses [CITEseq]
| PRJNA893694 | ENA
Project description:Human IRF1 governs phagocytic IFN-γ immunity to mycobacteria but not cell-intrinsic IFN-a/b immunity to viruses [scRNAseq]
| PRJNA893695 | ENA