期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 51, 页码 E10956-E10964出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1708252114
关键词
Mycobacterium tuberculosis; GEM T cells; CD1b; mycolate lipids; molecular dynamics
资金
- Public Health England
- US NIH Grant [R33AI102239]
- UK Medical Research Council Grant [MR/N006631/1]
- Cancer Research UK Grant [A23562]
- BBSRC [BB/J017302/1] Funding Source: UKRI
- EPSRC [EP/M022609/1, EP/L000253/1] Funding Source: UKRI
- MRC [MR/N006631/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J017302/1] Funding Source: researchfish
- Cancer Research UK [23562, 16997] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/L000253/1, EP/M022609/1, 976841] Funding Source: researchfish
- Medical Research Council [MR/N006631/1] Funding Source: researchfish
- National Institute for Health Research [CL-2011-26-004] Funding Source: researchfish
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in TB granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells.
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