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Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation

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Abstract

Mycobacterium tuberculosis (Mtb) establishes a persistent infection, despite inducing antigen-specific T-cell responses. Although T cells arrive at the site of infection, they do not provide sterilizing immunity. The molecular basis of how Mtb impairs T-cell function is not clear. Mtb has been reported to block major histocompatibility complex class II (MHC-II) antigen presentation; however, no bacterial effector or host-cell target mediating this effect has been identified. We recently found that Mtb EsxH, which is secreted by the Esx-3 type VII secretion system, directly inhibits the endosomal sorting complex required for transport (ESCRT) machinery. Here, we showed that ESCRT is required for optimal antigen processing; correspondingly, overexpression and loss-of-function studies demonstrated that EsxH inhibited the ability of macrophages and dendritic cells to activate Mtb antigen-specific CD4+ T cells. Compared with the wild-type strain, the esxH-deficient strain induced fivefold more antigen-specific CD4+ T-cell proliferation in the mediastinal lymph nodes of mice. We also found that EsxH undermined the ability of effector CD4+ T cells to recognize infected macrophages and clear Mtb. These results provide a molecular explanation for how Mtb impairs the adaptive immune response.

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Figure 1: ESCRT promotes antigen presentation by Mtb-infected macrophages.
Figure 2: ESCRT promotes antigen presentation by facilitating antigen processing.
Figure 3: EsxGHMt impairs antigen presentation.
Figure 4: Fewer ΔesxH c.f.u. are required to initiate proliferation in the MLNs and lungs.
Figure 5: EsxGHMt impairs priming of naive CD4+ T cells in vivo.
Figure 6: EsxH protects Mtb from CD4+ T-cell mediated killing.

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  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.

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Acknowledgements

We thank the New York University Cytometry Core at the Laura and Isaac Perlmutter Cancer Center (partially supported by a Cancer Center Support Grant, P30CA016087) for their assistance with flow cytometry, Beatrix Ueberheide and Jessica Chapman-Lim for assistance with proteomics (New York University Proteomics Resource Center), Michael Glickman (Memorial Sloan-Kettering Cancer Center) for the C7TCR Tg mice, BEI Resources, NIAID, NIH for Ag85B protein (Ag85B Recombinant Protein Reference Standard, NR-14870), and members of the Philips and Ernst laboratories, in particular Colette O'Shaughnessy and Ludovic Desvignes, for assistance and helpful discussions. This work was supported by National Institutes of Health grants R01s AI087682, AI026170, and AI098925, K08 AI119150-01 and UL1 TR000038.

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C.P.-C., and J.A.P. conceived and designed the study. C.P.-C. performed all the in vitro experiments with help from T.K., with the exception of the trafficking studies done by A.Z. C.P.-C. and S.S. designed and performed in vivo experiments. A.M. and H.S.P. created plasmids. J.M.T. and W.R.J. contributed the ΔesxH and Δpe5-ppe4 strains. C.P.-C. and P.S.G performed flow cytometry. C.P.-C. and J.A.P. interpreted the results and wrote the manuscript. J.D.E., W.R.J. and J.A.P. oversaw the project.

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Correspondence to William R. Jacobs Jr or Jennifer A. Philips.

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Portal-Celhay, C., Tufariello, J., Srivastava, S. et al. Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation. Nat Microbiol 2, 16232 (2017). https://doi.org/10.1038/nmicrobiol.2016.232

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