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T cell apoptosis is associated with defective cell-mediated effector functions in several infectious diseases. In tuberculosis, there is evidence that T cell apoptosis may be cytokine mediated, but the mechanisms are not clearly 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 that PBLs from healthy donors respond to sonicated Mycobacterium tuberculosis 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 linking these observations was tested. CD30 expression and TNF-α-mediated lymphocyte apoptosis were both down-regulated by inhibiting IL-4 in this model. TNFR-associated factor 2 (TRAF2) expression was down-regulated in CD30+ cells, and addition of anti-TNF-α Ab significantly reduced apoptosis in the CD30+ but not the CD30− population. These observations support the hypothesis that increased IL-4 expression in M. tuberculosis-activated lymphocytes promotes CD30 expression, which sensitizes the lymphocytes to TNF-α-mediated apoptosis via TRAF2 depletion. This may be one mechanism by which IL-4 is associated with immunopathological consequences in human tuberculosis.