A conserved human CD4+ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate
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.
Authors
- Nagatoshi Fujiwara (ORCID: https://orcid.org/0000-0001-5566-681X)
- Daisuke Motooka (ORCID: https://orcid.org/0000-0002-4616-9608)
- Kentaro Tanaka (ORCID: https://orcid.org/0000-0001-8645-6436)
- Yuki Sakai (ORCID: https://orcid.org/0000-0002-8427-4740)
- D. Branch Moody (ORCID: https://orcid.org/0000-0003-2306-3058)
- Ildiko Van Rhijn (ORCID: https://orcid.org/0000-0002-1446-5701)
- Masamichi Nagae (ORCID: https://orcid.org/0000-0002-5470-3807)
- Mika Hirose (ORCID: https://orcid.org/0000-0001-8991-587X)
- Hiroto Tamashima
- Xiuyuan Lu (ORCID: https://orcid.org/0000-0002-0784-2871)
- Go Hirai (ORCID: https://orcid.org/0000-0003-3420-555X)
- Yoshihiko Hoshino (ORCID: https://orcid.org/0000-0002-3132-0715)
- Minori Asa
- Shinsuke Inuki (ORCID: https://orcid.org/0000-0002-7525-1280)
- Takahiro Ikazaki
- Wakana Kusuhara
- Sho Yamasaki (ORCID: https://orcid.org/0000-0002-5184-6917)
- Takayuki Kato (ORCID: https://orcid.org/0000-0002-7210-9457)
- Eri Ishikawa (ORCID: https://orcid.org/0000-0002-4922-6751)
- Shiori Oka
- Takashi Yoshiyama
- Kota Kuraba
Institutions
- Brigham and Women's Hospital (US)
- Kyushu University (JP)
- Harvard University (US)
- Utrecht University (NL)
- Kyoto University (JP)
- Center of Molecular Immunology (Cuba) (CU)
- Kyoto Pharmaceutical University (JP)
- National Institute of Infectious Diseases (JP)
- Japan Anti Tuberculosis Association (JP)
- Microbial Chemistry Research Foundation (JP)
- Amsterdam University Medical Centers (NL)
- Protein Research Foundation (JP)
- Fukujuji Hospital (JP)
- Tokushima University (JP)
- Tezukayama University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-12-24
- DOI
- https://doi.org/10.1172/jci185443
- Citations
- 6
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- Japan Agency for Medical Research and Development
- Monash University
- National Institutes of Health
- Japan Society for the Promotion of Science
- Research Institute for Microbial Diseases, Osaka University