Mycobacterium tuberculosis suppresses protective Th17 responses during infection
- 1Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
- 2Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, United States
- 3Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, United States
Abstract
Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing Th1 CD4+ T cells are necessary but insufficient for protection against infection. In humans, the development of IL-17A-producing Th17 T cells correlates with protection; however, not all individuals develop a Th17 response. In mice, experimental vaccines can elicit protective Th17 cells, yet Th17s are rare in primary infection. Why Mtb fails to consistently elicit Th17s is unknown. Here, we identify factors suppressing Th17 responses during primary infection. We demonstrate that the lack of Th17 induction is independent of route and duration. Next, using Tbx21-deficient mice, we show that Mtb drives a Th1 response that is only partially protective and limits Th17 cell production in an IFN-γ-independent manner. We further reveal that the ESX-1 type VII secretion system and lipid phthiocerol dimycocerosate (PDIM) suppress Th17 responses. Infection with ESX-1 or PDIM mutants results in significantly increased Th17 T cells and IL-17A cytokine in the lungs, and infection of IL-17A-deficient animals partially restores virulence of ESX-1 and PDIM mutants. Although the ESX-1 secretion system and lipid PDIM elicit type I IFN, which can suppress Th17 differentiation, we find that suppression of Th17 is independent of type I IFN. Instead, ESX-1 and PDIM suppress production of IL-23, a cytokine that promotes Th17 differentiation, in dendritic cells found in mediastinal lymph nodes during Mtb infection. These findings define a new function of the ESX-1 secretion system and PDIM in Mtb virulence, a long-standing question in tuberculosis research.
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BibTeX
@article{zilinskas2026mycobacterium,
title = {{Mycobacterium tuberculosis suppresses protective Th17 responses during infection}},
author = {Alex Zilinskas and Amir Balakhmet and Douglas Fox and Heyuan Michael Ni and Carolina Agudelo and Helia Samani and Sarah A Stanley},
journal = {eLife},
year = {2026},
month = oct,
doi = {10.7554/elife.110008},
url = {https://doi.org/10.7554/elife.110008},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mycobacterium tuberculosis suppresses protective Th17 responses during infection
AU - Alex Zilinskas
AU - Amir Balakhmet
AU - Douglas Fox
AU - Heyuan Michael Ni
AU - Carolina Agudelo
AU - Helia Samani
AU - Sarah A Stanley
PY - 2026
DA - 2026/10/23
JO - eLife
DO - 10.7554/elife.110008
UR - https://doi.org/10.7554/elife.110008
AB - Mycobacterium tuberculosis (Mtb) causes more deaths annually than any other pathogen, yet an effective vaccine remains elusive. IFN-γ-producing Th1 CD4+ T cells are necessary but insufficient for protection against infection. In humans, the development of IL-17A-producing Th17 T cells correlates with protection; however, not all individuals develop a Th17 response. In mice, experimental vaccines can elicit protective Th17 cells, yet Th17s are rare in primary infection. Why Mtb fails to consistently elicit Th17s is unknown. Here, we identify factors suppressing Th17 responses during primary infection. We demonstrate that the lack of Th17 induction is independent of route and duration. Next, using Tbx21-deficient mice, we show that Mtb drives a Th1 response that is only partially protective and limits Th17 cell production in an IFN-γ-independent manner. We further reveal that the ESX-1 type VII secretion system and lipid phthiocerol dimycocerosate (PDIM) suppress Th17 responses. Infection with ESX-1 or PDIM mutants results in significantly increased Th17 T cells and IL-17A cytokine in the lungs, and infection of IL-17A-deficient animals partially restores virulence of ESX-1 and PDIM mutants. Although the ESX-1 secretion system and lipid PDIM elicit type I IFN, which can suppress Th17 differentiation, we find that suppression of Th17 is independent of type I IFN. Instead, ESX-1 and PDIM suppress production of IL-23, a cytokine that promotes Th17 differentiation, in dendritic cells found in mediastinal lymph nodes during Mtb infection. These findings define a new function of the ESX-1 secretion system and PDIM in Mtb virulence, a long-standing question in tuberculosis research.
SN - 2050-084X
ER -