COMPARATIVE-ANALYSIS OF ALPHA-BETA AND GAMMA-DELTA T-CELL ACTIVATION BY MYCOBACTERIUM-TUBERCULOSIS AND ISOPENTENYL PYROPHOSPHATE

Phosphorylated nonpeptide compounds have recently been identified as p otent mycobacteria-derived ligands for human V gamma 9/V delta 2-expre ssing gamma delta T cells. Crude mycobacterial extracts also contain p rotein antigens which stimulate CD4 alpha beta T cells to produce grow th factors that are used by gamma delta T cells for clonal expansion. We have investigated the dynamics in vitro of expansion of CD4 T cells and V gamma 9 cells in cultures of peripheral blood mononuclear cells stimulated with synthetic isopentenyl pyrophosphate (IPP) in the abse nce or presence of additional sri mull. The results indicated that fol lowing stimulation with IPP, gamma delta T cells express CD25 and CD69 antigens, but fail to proliferate unless growth factors are provided exogenously or endogenously through activation of CD4 T cells by addit ional stimuli such as tetanus toroid, alloantigen, or superantigens. F urthermore, the presence of antigen presenting cells are required for expansion of gamma delta T cells. In response to IPP stimulation, puri fied CD4 T cells neither express CD25 or CD69, nor do they proliferate even in the presence of exogenous IL-2. Apart from IL-2, IL-15 and, l ess efficiently, IL-4, IL-7, and IL-12 can contribute to cellular expa nsion of IPP-reactive V gamma 9 cells. Together, the results demonstra te that peripheral blood gamma delta T cells proliferate in response t o IPP only if CD4 T cells are simultaneously activated by an additiona l stimulus. This mechanism provides a tight control of the reactivity of gamma delta T cells towards phosphorylated nonpeptide antigens.