TY - JOUR
T1 - Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T-cell activation
AU - Portal-Celhay, Cynthia
AU - Tufariello, Joann M.
AU - Srivastava, Smita
AU - Zahra, Aleena
AU - Klevorn, Thais
AU - Grace, Patricia S.
AU - Mehra, Alka
AU - Park, Heidi S.
AU - Ernst, Joel D.
AU - Jacobs, William R.
AU - Philips, Jennifer A.
N1 - Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.
PY - 2016/12/5
Y1 - 2016/12/5
N2 - 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.
AB - 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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U2 - 10.1038/nmicrobiol.2016.232
DO - 10.1038/nmicrobiol.2016.232
M3 - Article
C2 - 27918526
AN - SCOPUS:85002389010
SN - 2058-5276
VL - 2
JO - Nature Microbiology
JF - Nature Microbiology
M1 - 16232
ER -