CD1 molecules are antigen presenting molecules that present lipids to T cells. Humans express both group 1 and group 2 CD1 molecules, while mice express only group 2 CD1. To study the in vivo function of group 1 CD1 T cells, we have developed a novel animal model by introducing the entire human group 1 CD1 locus into the mouse (hCD1Tg). Mycobacterium tuberculosis (Mtb) lipid antigens with unique structural features have been shown to stimulate group 1 CD1 T cells. However, the relative contribution of group 1 CD1 T cells to specific immunity is unknown. We determined the immunogenicity of Mtb lipid antigens by quantifying individual lipid-specific T cell frequencies in Mtb-infected hCD1Tg mice. Unlike Mtb-peptide specific T cells that are dominated by few epitopes, group 1 CD1-restricted T cells responded to several Mtb lipid antigens. The responses to phosphatidyl mannosides 6 (PIM6), lipoarabinomannan (LAM), mycolic acid (MA), and mycolic acid methyl esters (MAME) were more prominent than others.

 A large proportion of the group 1 CD1-restricted T cell lines isolated so far are autoreactive, raising the possibility that these T cells play a physiological role in immunity. We found that autoreactive group 1 CD1-restricted T cells dominated the group 1 CD1-restricted T cell responses in the lung at the chronic phase of Mtb infection. Moreover, autoreactive group 1 CD1-restricted T cells had different activation kinetics than group 2 CD1-restricted iNKT cells during Mtb infection, suggesting they play a different role during Mtb infection. Autoreactive group 1 CD1-restricted T cells had heterogeneous co-receptor expression, showed diverse TCR usage and produced multiple cytokines. These T cells were found to be KLRG1⁺ suggesting that they may be terminally differentiated.  Together, our data provides information about the dynamics and in vivo function of group 1 CD1-restricted T cells during Mtb infection.