Human Purified Protein Derivative-Specific CD4+ T Cells Use Both CD95-Dependent and CD95-Independent Cytolytic Mechanisms

• Published in: The Journal of immunology (1950) Vol. 160; no. 5; pp. 2374 - 2379
• Main Authors: Lewinsohn, David M, Bement, Teresa T, Xu, Jiangchun, Lynch, David H, Grabstein, Kenneth H, Reed, Steven G, Alderson, Mark R
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-03-1998
• Subjects: Antibodies, Blocking - pharmacology; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - immunology; Cell Line; Clone Cells; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Epitopes - immunology; Esterases - metabolism; Fas Ligand Protein; fas Receptor - biosynthesis; fas Receptor - immunology; fas Receptor - physiology; Humans; Jurkat Cells; Lymphocyte Activation - genetics; Macrophages - immunology; Membrane Glycoproteins - genetics; Monocytes - immunology; Perforin; Pore Forming Cytotoxic Proteins; RNA, Messenger - biosynthesis; T-Lymphocytes, Cytotoxic - enzymology; T-Lymphocytes, Cytotoxic - immunology; Tuberculin - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.160.5.2374

CTL, both CD4+ and CD8+, are essential in the eradication of intracellular pathogens. Data generated using murine T cells have suggested a critical role for CD95 (Fas, Apo-1) in CD4+ T cell-induced apoptosis of target cells. In contrast, CD8+ CTL predominantly use the perforin/granzyme lytic pathway. At present little is known about the mechanism of CD4+ CTL lytic function during intracellular infection in humans. We have used human CD4+ T cells specific for purified protein derivative (PPD) of Mycobacterium tuberculosis to explore whether CD95 is the dominant cytolytic mechanism. PPD-reactive CD4+ clones efficiently lysed Ag-pulsed autologous monocytes, adherent macrophages, and EBV-transformed B cells. Addition of an antagonistic CD95 Ab had a minimal effect on cytolysis, whereas addition of MgEGTA to block perforin/granzyme resulted in complete inhibition of killing. In contrast, lysis of activated peripheral blood B cells could be partially blocked with the antagonistic CD95 Ab. Supporting these observations, monocytes, macrophages, and EBV-transformed B cells were not lysed by an agonistic CD95 Ab. Activated B cells were readily lysed by the agonistic CD95 Ab. T cell clones triggered through the TCR with anti-CD3 were capable of lysing the CD95-sensitive Jurkat T cell line in a CD95-dependent manner, but were also able to release granzymes. We conclude that human CD4+ T cells are capable of lysing PPD-pulsed targets using both perforin/granzyme and CD95 pathways. The contribution of CD95 is strictly dependent on target cell susceptibility to CD95-mediated killing.