Generation of nitric oxide by the inducible nitric oxide synthase protects gamma delta T cells from Mycobacterium tuberculosis-induced apoptosis.
Gamma delta T cells are early recruited into mycobacterial lesions. Upon microbial Ag recognition, gamma delta cells secrete cytokines and chemokines and undergo apoptosis via CD95/CD95 ligand (CD95L) interaction, possibly influencing the outcome of infection and the characteristics of the disease. In this paper we show that activated phagocytes acquire, upon challenge with Mycobacterium tuberculosis, the ability to inhibit M. tuberculosis-induced gamma delta cell apoptosis. Apoptosis protection was due to NO because it correlated with NO synthase (NOS)-2 induction and activity in scavenger cells and was abrogated by NOS inhibitors. Furthermore, the NO donor S-nitrosoacetylpenicillamine mimicked the effect of enzyme induction. NO left unaffected the expression of CD95 and CD95L, suggesting interference with an event ensuing CD95/CD95L interaction. NO was found to interfere with the intracellular accumulation of ceramide and the activation of caspases, which were involved in gamma delta T cells apoptosis after M. tuberculosis recognition. We propose that NO generated by infected macrophages determines the life span and therefore the function of lymphocytes at the infection site, thus linking innate and adaptive immunity.
Laboratory of Tumor Immunology, Receptor Biochemistry Unit, DIBIT, Laboratory of Microbiology, Scientific Institute H. S. Raffaele, Milan, Italy.
C
C
Sciorati
P
P
Rovere
M
M
Ferrarini
C
C
Paolucci
S
S
Heltai
R
R
Vaiani
E
E
Clementi
A A
AA
Manfredi
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D002999:Clone Cells; D015536:Down-Regulation / Q000276:immunology; D053222:Fas Ligand Protein; D006801:Humans; D007113:Immunity, Innate; D007424:Intracellular Fluid / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D017628:Microglia; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010586:Phagocytes / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology
D000942:Antigens, Bacterial; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019014:fas Receptor; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse