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TitleA conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate.
Journal, issue, pagesJ Clin Invest, Vol. 135, Issue 6, 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 (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most ...Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a 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, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed 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 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.5 - 3.18 Å
Structure data

60321

8zox

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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