Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Yang, R.; Mele, F.; Worley, L.; Langlais, D.; Rosain, J.; Benhsaien, I.; Elarabi, H.; Croft, C. A.; Doisne, J.-M.; Zhang, P.; Weisshaar, M.; Jarrossay, D.; Latorre, D.; Shen, Y.; Han, J.; Gruber, C.; Markle, J.; Ali, F. A.; Rahman, M.; Khan, T.; Seeleuthner, Y.; Kerner, G.; Husquin, L. T.; Maclsaac, J.; Jeljeli, M.; Ailal, F.; Kobor, M.; Oleaga-Quintas, C.; Roynard, M.; Bourgey, M.; Baghdadi, J. E.; Boisson-Dupuis, S.; Puel, A.; Batteux, F.; Rozenberg, F.; Marr, N.; Pan-Hammarstrom, Q.; Bogunovic, D.; Quintana-Murci, L.; Carroll, T.; Ma, C.; Abel, L.; Bousfiha, A.; Di Santo, J.; Glimcher, L. H

doi:10.1101/2020.08.31.274589

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bioRxiv · 10.1101/2020.08.31.274589

Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

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Abstract

Inborn errors of human IFN-{gamma} immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and V{delta}2+ {gamma}{delta} T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-{gamma}. Other IFN-{gamma}-producing lymphocyte subsets however develop normally, but with low levels of IFN-{gamma} production, with exception of V{delta}2- {gamma}{delta} T lymphocytes, which produce normal amounts of IFN-{gamma} in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-{gamma} normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-{gamma} production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and V{delta}2+ {gamma}{delta} T cells), with mycobacterial-specific, IFN-{gamma}-producing, purely adaptive {beta} TH1* cells unable to compensate for this deficit.

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Yang, R., Mele, F., Worley, L., Langlais, D., Rosain, J., Benhsaien, I., Elarabi, H., Croft, C. A., Doisne, J.-M., Zhang, P., Weisshaar, M., Jarrossay, D., Latorre, D., Shen, Y., Han, J., Gruber, C., Markle, J., Ali, F. A., Rahman, M., Khan, T., Seeleuthner, Y., Kerner, G., Husquin, L. T., Maclsaac, J., Jeljeli, M., Ailal, F., Kobor, M., Oleaga-Quintas, C., Roynard, M., Bourgey, M., Baghdadi, J. E., Boisson-Dupuis, S., Puel, A., Batteux, F., Rozenberg, F., Marr, N., Pan-Hammarstrom, Q., Bogunovic, D., Quintana-Murci, L., Carroll, T., Ma, C., Abel, L., Bousfiha, A., Di Santo, J., Glimcher, L. H. 2020-08-31. Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria. https://doi.org/10.1101/2020.08.31.274589

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