While T cells are canonically activated through the T cell receptor upon antigen recognition, they can also undergo antigen-independent activation by proinflammatory cytokines. This ‘bystander activation’ may be host protective during M. tuberculosis (Mtb) infection. CD1b restricted T cells recognize the mycobacterial cell wall lipids mycolic acid (MA) and glucose monomycolate (GMM) presented by non-polymorphic CD1b molecules. While these T cells are activated after recognition of cognate antigen during Mtb infection, the ability of CD1b specific T cells to undergo bystander activation and contribute to Mtb immunity is unknown. We first profiled the antigen-independent responses of CD1b GMM and MA specific T cell lines after stimulation with exogenous IL-12, IL-15, and IL-18. While both cell lines responded to cytokine stimulation, the CD1b MA T cell line had 1.6-fold higher IFNg expression and higher levels of IL-18 receptor (IL-18R) expression (46.6% vs 2.15%) than the CD1b GMM cell line. Correspondingly, IFNg secretion was inhibited by an IL-18R blocking antibody in a dose dependent manner. We next evaluated bystander responses of ex-vivo lipid specific T cell subsets from the peripheral blood of Mtb-infected South African adolescents. We found that CD1b MA T cells had 1.5-fold higher IFNg secretion (p=0.001) and 3.4-fold higher induced granzyme B (GzmB) expression (p=0.00015) than CD1b GMM specific T cells. Further, CD1b MA specific T cells had higher expression of all polyfunctional phenotypes. IL-18R expression on ex-vivo CD1 restricted T cells correlated with higher levels of IFNg secretion (R=0.65, p<0.0001). Our data demonstrates that CD1b GMM and MA specific T cells can undergo activation independently of antigen recognition and further express polyfunctional anti-bacterial effector functions in response to bystander activation.