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.

Abstract

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.

• Authors: B Li, H Bassiri, M D Rossman, P Kramer, A F Eyuboglu, M Torres, E Sada, T Imir, S R Carding
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 161 Issue 3 Pg. 1558-67 (Aug 01 1998) ISSN: 0022-1767 [Print] United States
• PMID: 9686624 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Blocking
• FASLG protein, human
• Fas Ligand Protein
• Interleukin-2
• Ligands
• Membrane Glycoproteins
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Antigen, T-Cell, gamma-delta
• Tumor Necrosis Factor-alpha
• fas Receptor

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Blocking (pharmacology)
• Apoptosis (immunology)
• Cells, Cultured
• Child
• Child, Preschool
• Fas Ligand Protein
• Female
• Humans
• Immunity, Innate
• Interleukin-2 (physiology)
• Ligands
• Lymphocyte Activation
• Male
• Membrane Glycoproteins (biosynthesis, immunology, physiology)
• Middle Aged
• Mycobacterium tuberculosis (immunology)
• Receptors, Antigen, T-Cell, alpha-beta (immunology)
• Receptors, Antigen, T-Cell, gamma-delta (immunology)
• T-Lymphocyte Subsets (immunology, metabolism, pathology)
• Tuberculosis, Pulmonary (drug therapy, immunology, pathology)
• Tumor Necrosis Factor-alpha (physiology)
• fas Receptor (biosynthesis, immunology, physiology)