The Role of Group 1 CD1-restricted T Cells in Infectious Disease

Humans but not muroid rodents express group 1 CD1 molecules, CD1a, b, and c. Interestingly, group 1 CD1 molecules are closely tied to anti-mycobacterial immunity because they can present a variety of mycobacteria-derived lipid antigens and group 1 CD1-specific T cell responses are detected at higher frequencies in Mycobacterium tuberculosis (Mtb) infected individuals. However, due to the lack of a small animal model, there is no direct evidence of the protective capacity of group 1 CD1-restricted T cells. Therefore, my lab generated a transgenic mouse model (hCD1Tg) that harbored the human group 1 CD1 locus and supported the development of group 1 CD1-restricted T cells. Infection of hCD1Tg mice with Mtb generated group 1 CD1-restricted Mtb lipid antigen-specific T cell responses. In addition, adoptive transfer of group 1 CD1-restricted T cells conferred protection against infection. Taken together, these data indicate that group 1 CD1-restricted T cells play a role in adaptive immunity to Mtb and could serve as vaccine targets. This proposal seeks to further elucidate the role of group 1 CD1-restricted T cells in different stages of Mtb infection and evaluate whether group 1 CD1-restricted T cells play a role in immunity against other bacterial pathogens. In aim 1, we will evaluate whether memory group 1 CD1-restricted T cells can be generated in secondary Mtb infection and determine the molecular and cellular events associated with the induction of memory group 1 CD1-restricted T cells. While group 1 CD1-restricted Mtb lipid antigen-specific T cells are present during early stages of Mtb infection, autoreactive group 1 CD1-restricted T cells expand at later stages in the lung of infected mice. In aim 2, we will evaluate the surface phenotype, functional properties of these T cells and determine whether they play a protective role during Mtb infection. In addition, we will compare the activation requirements of autoreactive and Mtb lipid-specific group 1 CD1-restri