INVOLVEMENT OF THE FAS FAS LIGAND PATHWAY IN ACTIVATION-INDUCED CELL-DEATH OF MYCOBACTERIA-REACTIVE HUMAN GAMMA-DELTA T-CELLS - A MECHANISMFOR THE LOSS OF GAMMA-DELTA T-CELLS IN PATIENTS WITH PULMONARY TUBERCULOSIS/

Although the identity of T cells involved in the protection against My cobacterium tuberculosis (Mtb) in humans remain unknown, patients with pulmonary tuberculosis (TB) hare reduced numbers of Mtb-reactive, V g amma 9(+)/V delta 2(+) T cells in their blood and lungs. sere ne have determined whether this gamma delta T loss is a consequence of Mtb Ag- mediated activation-induced cell death (AICD). Using a DNA polymerase- mediated dUTP nick translation labeling assay, 5% or less of freshly i solated CD4(+) alpha beta or gamma delta T cells from normal healthy i ndividuals and TB patients were apoptotic. However, during culture Mtb Ags, induced apoptosis in a large proportion of V gamma 9(+)/V delta 2(+) peripheral blood T cells from healthy subjects (30-45%) and TB pa tients (55-68%); this was increased further in the presence of IL-2, B y contrast, anti-CD3 did not induce any significant level of apoptosis In gamma delta T cells from healthy subjects or TB patients. Mtb Ag s timulation rapidly induced Fas and Fas ligand (FasL) expression by gam ma delta T cells, and in the presence of metalloproteinase-inhibitors >70% of gamma delta T cells were FasL(+). Blockade of Fas-FasL interac tions reduced the level of Mtb-mediated gamma delta T cell apoptosis b y 75 to 80%. Collectively, these findings demonstrate that Mtb-reactiv e gamma delta T cells are more susceptible to AICD and that the Fas-Fa sL pathways of apoptosis is involved. AICD of gamma delta T cells, the refore, provides an explanation for the loss of Mtb-reactive T cells d uring mycobacterial infection.