Investigating the functional role of CD1 expression and defining protective and pathogenic CD1c-immunity in tuberculosis.

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Due to the lack of an effective vaccine and the rise of drug resistant and multidrug resistant strains, Mycobacterium tuberculosis (Mtb) infection, which causes Tuberculosis (TB), remains one of the leading causes of death worldwide. CD1c-restricted T cells make for exciting potential targets for future TB vaccines due to the ability of the non-polymorphic nature of the CD1c antigen presenting system to mediate responses to lipid antigens, such as those of lipid-rich Mtb cell wall, whilst accounting for the high levels of immune heterogeneity associated with immune response in TB. It is believed that they may play a role in in the host immune response to TB, however, considering a large proportion of CD1crestricted T cells are autoreactive, it is not known if they are protective or pathogenic. Making their study challenging, culturing CD1c-restricted T cells is difficult. To answer the hypothesis "CD1cimmunity is protective during the host response to TB", I have developed a methodology of generating pure CD1c-restricted T cell lines and have then conducted functional studies by co-culturing T cell lines with Mtb infected CD1c+ target cells. Data collected thus far shows that CD1c-restricted T cells become significantly more activated with Mtb infection and have the ability to kill CD1c+ targets. Previous studies have shown that Mtb infection results in a down regulation of group 1 CD1 expression. This has led to suggestions that Mtb may do so in order to subvert group 1 CD1-mediated immune responses enabling it to survive within host immune cells. To answer the hypothesis "Mtb infection can influence the CD1 expression of antigen presenting cells", I infected antigen presenting cells with Mtb at a multiplicity of infection (MOI) suitable for functional studies and measured group 1 CD1 expression. Compared to uninfected antigen presenting cells, expression of all group 1 CD1 molecules was reduced. Recent work in the lab using CD1c-endo tetramers and single cell TCR sequencing has independently generated multiple Vgamma9Vdelta2 TCRs derived from different donors which are believed to be CD1crestricted, surprising, as CD1c is not a known ligand. I have also begun preliminary investigations to answer the hypothesis "CD1c is a ligand for Vgamma9Vdelta2 T cells".