Group 1 CD1 molecules present microbial and self-lipid antigens to several distinct subsets of T cells. Humans, but not muroid rodents, express group 1 CD1 molecules, making the in vivo functional study of these T cells difficult. To overcome this challenge, we have generated human CD1 transgenic mice (hCD1Tg) that express CD1a, CD1b, and CD1c in a pattern similar to that seen in humans. In addition, we have generated two TCR transgenic mouse models, one expresses TCR from a CD1b-restricted autoreactive T cell clone (HJ1Tg) and the other expresses TCR specific for CD1b/mycolic acid (DN1Tg). We found these two group 1 CD1-restricted T cell subsets exhibit distinct phenotypes, even though they share a similar developmental pathway. Both DN1 and HJ1 T cells can be activated in response to Mycobacterium tuberculosis (Mtb) infection. Upon adoptive transfer of DN1 T cells to Mtb-infected hCD1Tg mice, DN1 T cells are first activated in the mediastinal lymph nodes and exhibit faster kinetics than Mtb Ag85B-specific conventional CD4+ T cells. Furthermore, activated DN1 T cells exhibit polyfunctional characteristics, accumulate in lung granulomas, and protect against Mtb infection. Compared to DN1 T cells, adoptive transfer of HJ1 T cells provides lesser protection against Mtb infection. To further explore the in vivo function of CD1b-autoreactive T cells, we examined their role under conditions of hyperlipidemia by crossing hCD1Tg/HJ1Tg mice into the ApoE deficient background. Interestingly, hCD1Tg/HJ1Tg/ApoE-/- mice develop severe psoriasis like skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine milieu. They also show significantly increased CD1b expression and polar lipid accumulation in the skin as compared to wildtype counterparts in the ApoE sufficient background. This suggests that the presence of excess lipids in the skin results in activation of the CD1b-autoreacitve T cells, leading to the development of inflammatory skin diseases.