Mycobacterium-Specific γ9δ2 T Cells Mediate Both Pathogen-Inhibitory and CD40 Ligand-Dependent Antigen Presentation Effects Important for Tuberculosis Immunity

Numerous pathogens, including Mycobacterium tuberculosis, can activate human gamma(9)delta(2) T cells to proliferate and express effector mechanisms. gamma(9)delta(2) T cells can directly inhibit the growth of intracellular mycobacteria and may also act as antigen-presenting cells (APC). Despite evidence for gamma delta T cells having the capacity to function as APC, the mechanisms involved and importance of these effects on overall tuberculosis (TB) immunity are unknown. We prepared M. tuberculosis-specific gamma(9)delta(2) T cell lines to study their direct protective effects and APC functions for M. tuberculosis-specific alpha beta T cells. The direct inhibitory effects on intracellular mycobacteria were measured, and the enhancing effects on proliferative and effector responses of alpha beta T cells assessed. Furthermore, the importance of cell-to-cell contact and soluble products for gamma(9)delta(2) T cell effector responses and APC functions were investigated. We demonstrate, in addition to direct inhibitory effects on intracellular mycobacteria, the following: (i) gamma(9)delta(2) T cells enhance the expansion of M. tuberculosis-specific alpha beta T cells and increase the ability of alpha beta T cells to inhibit intracellular mycobacteria; (ii) although soluble mediators are critical for the direct inhibitory effects of gamma(9)delta(2) T cells, their APC functions do not require soluble mediators; (iii) the APC functions of gamma(9)delta(2) T cells involve cell-to-cell contact that is dependent on CD4(0)-CD40 ligand (CD40L) interactions; and (iv) fully activated CD4(+) alpha beta T cells and gamma(9)delta(2) T cells provide similar immune enhancing/APC functions for M. tuberculosis-specific T cells. These effector and helper effects of gamma(9)delta(2) T cells further indicate that these T cells should be considered important new targets for new TB vaccines.