Il-4 influences apoptosis of mycobacterium-reactive lymphocytes in the presence of TNF-alpha.
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-alpha-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-alpha 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-alpha-mediated apoptosis via TRAF2 depletion. This may be one mechanism by which IL-4 is associated with immunopathological consequences in human tuberculosis.
Seah
G T
GT
Department of Medical Microbiology, Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, 46 Cleveland Street, London W1T 4JF, United Kingdom.
Rook
G A
GA
D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D018106:CD28 Antigens / Q000502:physiology; D002458:Cell Fractionation; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D017730:Ki-1 Antigen / Q000096:biosynthesis / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D000942:Antigens, Bacterial; D015415:Biomarkers; D018106:CD28 Antigens; D007106:Immune Sera; D017730:Ki-1 Antigen; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4