A conserved human CD4⁺ T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate

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Abstract

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

Yuki 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