IL-4 influences apoptosis of mycobacterium-reactive lymphocytes in the presence of TNF-alpha

T cell apoptosis is associated with defective cell-mediated effector functi ons in several infectious diseases. In tuberculosis, there is evidence that T cell apoptosis may be cytokine mediated, but the mechanisms are not clea rly understood. Type 2 cytokines have recently been associated with disease extent in human tuberculosis, but they have not previously been linked to apoptosis in mycobacterium-reactive T cells. This study presents evidence t hat PBLs from healthy donors respond to sonicated Mycobacterium tuberculosi s Ags with increased IL-4 gene activation, CD30 expression, and apoptosis. The changes were significantly greater than those observed when cells were stimulated with Ags from nonpathogenic Mycobacterium vaccae. A hypothesis l inking these observations was tested. CD30 expression and TNF-alpha -mediat ed lymphocyte apoptosis were both down-regulated by inhibiting IL-4 in this model. TNFR-associated factor 2 (TRAF2) expression was down-regulated in C D30(+) cells, and addition of anti-TNF-alpha Ab significantly reduced apopt osis in the CD30(+) but not the CD30(-) population. These observations supp ort the hypothesis that increased IL-4 expression in M. tuberculosis-activa ted lymphocytes promotes CD30 expression, which sensitizes the lymphocytes to TNF-alpha -mediated apoptosis via TRAF2 depletion. This may be one mecha nism by which IIA is associated with immunopathological consequences in hum an tuberculosis.