Involvement of the Fas/Fas ligand pathway in activation-induced cell death of mycobacteria-reactive human gamma delta T cells: a mechanism for the loss of gamma delta T cells in patients with pulmonary tuberculosis.
Although the identity of T cells involved in the protection against Mycobacterium tuberculosis (Mtb) in humans remain unknown, patients with pulmonary tuberculosis (TB) have reduced numbers of Mtb-reactive, V gamma 9+/V delta 2+ T cells in their blood and lungs. Here we have determined whether this gamma deltaT 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 isolated CD4+ alpha beta or gamma delta T cells from normal healthy individuals 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 patients (55-68%); this was increased further in the presence of IL-2. By contrast, anti-CD3 did not induce any significant level of apoptosis in gamma delta T cells from healthy subjects or TB patients. Mtb Ag stimulation rapidly induced Fas and Fas ligand (FasL) expression by gamma delta T cells, and in the presence of metalloproteinase-inhibitors >70% of gamma delta T cells were FasL+. Blockade of Fas-FasL interactions reduced the level of Mtb-mediated gamma delta T cell apoptosis by 75 to 80%. Collectively, these findings demonstrate that Mtb-reactive gamma delta T cells are more susceptible to AICD and that the Fas-FasL pathways of apoptosis is involved. AICD of gamma delta T cells, therefore, provides an explanation for the loss of Mtb-reactive T cells during mycobacterial infection.
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
B
B
Li
H
H
Bassiri
M D
MD
Rossman
P
P
Kramer
A F
AF
Eyuboglu
M
M
Torres
E
E
Sada
T
T
Imir
S R
SR
Carding
D000293:Adolescent; D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007376:Interleukin-2 / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D019138:Antibodies, Blocking; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008024:Ligands; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor