Invited Speaker CD1-MR1 Workshop 2025

Identification of conserved CD1b motif (RExxD) that interacts with TRBV4-1 (#4)

Minori Asa 1 , Yuki Sakai 1 , Sho Yamasaki 1 2 3
  1. Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
  2. Laboratory of Molecular Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan
  3. Center for Infectious Disease Education and Research (CiDER), Osaka University, Suita, Osaka, Japan

CD1b-restricted T cells recognize various lipid antigens, including mycobacterial cell wall lipids. Among 26 published CD1b-restricted TCRs, 42% contain TRBV4-1 regardless of their cognate antigens (1).　We recently reported another CD1b-restricted T cell subset recognizing trehalose monomycolate (TMM). 83% of TMM-specific T cell clones also expressed TRBV4-1, whereas TRAV gene usage was diverse. Despite the biased TCRβ usage by CD1b-restricted TCRs, structural basis for this skewing remained unclear.

Ternary complex structure of a CD1b-TMM-TCR revealed that TCRβ loops are proximal to CD1b rather than TMM. CDR1, 2 and 3 loops of TRBV4-1 interact with three amino acids located in the α1 helix of CD1b (termed the 79RExxD83 motif), whereas the TCRα chain mainly interacts with TMM. Indeed, alanine substitutions of RExxD residues impaired TMM recognition by 5 different TCRs.

These results suggest that RExxD motif is essential for TRBV4-1 recognition of CD1b. Similar TRBV4-1 skew has been reported for CD1c-restricted T cells (2), which might be due to the conservation of this motif in the same region of CD1c. Therefore, this charged patch may contribute to preferential usage of TRBV4-1 in CD1-restricted T cells.

  1. Reinink et al., The Journal of Immunology 203.12 (2019): 3395-3406.
  2. Guo et al., The Journal of Immunology 200.2 (2018): 500-511.