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TitleA conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate.
Journal, issue, pagesJ Clin Invest, Year 2024
Publish dateDec 24, 2024
AuthorsYuki Sakai / Minori Asa / Mika Hirose / Wakana Kusuhara / Nagatoshi Fujiwara / Hiroto Tamashima / Takahiro Ikazaki / Shiori Oka / Kota Kuraba / Kentaro Tanaka / Takashi Yoshiyama / Masamichi Nagae / Yoshihiko Hoshino / Daisuke Motooka / Ildiko Van Rhijn / Xiuyuan Lu / Eri Ishikawa / D Branch Moody / Takayuki Kato / Shinsuke Inuki / Go Hirai / Sho Yamasaki /
PubMed AbstractMycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of ...Mycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, antigenicity of most adjuvantic lipids are unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activates human T cells bearing a unique ɑβTCR. This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA sequencing using newly established CD1b-TMM tetramers revealed that TMM-specific T cells are present as CD4+ effector memory T cells in the periphery of uninfected donors, but express IFNγ, TNF and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells are detected in cord blood and PBMCs of non-BCG-vaccinated donors, but are expanded in active tuberculosis patients. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively-charged CDR3ɑ and long CDR3β regions. These results indicate that humans have a commonly-shared and pre-formed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.
External linksJ Clin Invest / PubMed:39718834
MethodsEM (single particle) / X-ray diffraction
Resolution2.5 - 3.18 Å
Structure data

EMDB-60321, PDB-8zox:
3D structure of Y-50 TCR-TMM-CD1b ternary complex
Method: EM (single particle) / Resolution: 3.18 Å

PDB-8xub:
Crystal structure of Y-50 TCR
Method: X-RAY DIFFRACTION / Resolution: 2.5 Å

PDB-8zo4:
Crystal structure of Tfh TCR ectodomain thermostable mutant
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-SO4:
SULFATE ION

ChemComp-HOH:
WATER

ChemComp-6UL:
TETRACOSYL PALMITATE

ChemComp-GLC:
alpha-D-glucopyranose

PDB-1l2b:
MutM (Fpg) DNA End-Product Structure

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / TCR complex / T cell receptor / ecotodomain / thermostable mutant

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