CD1 molecules can bind mycobacterial lipids and activate T cells. However, since group 1 CD1 molecules are absent in mice, our understanding of CD1-restricted T cell function and differentiation remains limited. Recently, we performed comprehensive single-cell TCR analysis of human T cells responding to total mycobacterial lipids and identified a CD1b-restricted T cell subset that recognize trehalose monomycolate (TMM), a glycolipid abundant in the mycobacterial cell wall. These T cells shared a characteristic TCR motif suited to recognizing the bulky trehalose moiety and were found in multiple individuals. Single-cell analysis revealed that these cells exhibit effector memory phenotype in peripheral blood of healthy donors and upregulate cytotoxicity-associated genes, such as PRF1, GNLY and GZMB, upon ex vivo TMM stimulation. Furthermore, TMM-specific T cells in active tuberculosis patients also expressed cytotoxic effector markers.
To investigate the function of these T cells in vivo, we examined CD1b-restricted T cells in cynomolgus macaques. TMM-CD1b tetramer-positive (TMM-CD1b-tet+) T cells were detected in the peripheral blood of macaques and appeared as a clearly stained population within CD4+ CD161+ T cells in lymph nodes and spleen. Moreover, intratracheal administration of TMM increased the frequency of TMM-CD1b-tet+ T cells and these T cells showed cytotoxic potential.
Thus, the TMM-specific T cell subset is conserved among primates and utilizing non-human primate infection models enables evaluation of vaccine efficacy. Elucidating the detailed mechanisms underlying the memory potential and cytotoxicity of lipid-reactive T cells will contribute to the development of lipid-based vaccine strategies.