8zo4
Crystal structure of Tfh TCR ectodomain thermostable mutant
Structural highlights
Publication Abstract from PubMedMycobacterium 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 abetaTCR. 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 IFNgamma, 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 CDR3a and long CDR3beta 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. A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant, trehalose monomycolate.,Sakai Y, Asa M, Hirose M, Kusuhara W, Fujiwara N, Tamashima H, Ikazaki T, Oka S, Kuraba K, Tanaka K, Yoshiyama T, Nagae M, Hoshino Y, Motooka D, Van Rhijn I, Lu X, Ishikawa E, Moody DB, Kato T, Inuki S, Hirai G, Yamasaki S J Clin Invest. 2024 Dec 24:e185443. doi: 10.1172/JCI185443. PMID:39718834[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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