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

Cynthia Portal-Celhay, Joann M. Tufariello, Smita Srivastava, Aleena Zahra, Thais Klevorn, Patricia S. Grace, Alka Mehra, Heidi S. Park, Joel D. Ernst, William R. Jacobs, Jennifer A. Philips

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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.

Original languageEnglish (US)
Article number16232
JournalNature Microbiology
Volume2
DOIs
StatePublished - Dec 5 2016

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Portal-Celhay, C., Tufariello, J. M., Srivastava, S., Zahra, A., Klevorn, T., Grace, P. S., Mehra, A., Park, H. S., Ernst, J. D., Jacobs, W. R., & Philips, J. A. (2016). Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation. Nature Microbiology, 2, [16232]. https://doi.org/10.1038/nmicrobiol.2016.232