T-cell cytotoxicity of human Schwann cells: TNFalpha promotes fasL-mediated apoptosis and IFN gamma perforin-mediated lysis.
The ability of resident cells to induce apoptosis of invading immune cells is a major regulatory factor operating in immune-privileged tissues, including the nervous system. We investigated the cellular and molecular factors participating in modulation of immune response in peripheral nerves, focusing on two cytotoxic pathways: fas ligand (fasL) and perforin. fasL and perforin expression was found by immunochemistry on Schwann cells (Sc) in nerve biopsies from patients with chronic inflammatory demyelinating polyneuritis and on human Sc cultures. Treatment of Sc with tumor necrosis factor (TNF) alpha and interferon (IFN) gamma upregulated the expression of both molecules. In a coculture model, Sc exposed to TNFalpha or IFN gamma were able to induce both apoptotic and lytic injury of T-lymphocytes. Inactivation of fasL with the neutralizing antibody NOK-2 abolished T-cell apoptosis induced by Sc treated with TNFalpha, but not by Sc treated with IFN gamma. Conversely, T-cell lysis was significantly decreased when IFN gamma-activated Sc were treated with concanamycin A, which inhibited perforin release. At variance with T-lymphocytes, B-cells were less sensitive to cytokine-treated Sc toxicity. Thus, Sc exposed to inflammatory cytokines have the capacity of inducing selective damage of T-lymphocytes and have the potential of regulating the immune response in the peripheral nervous system.
Bonetti
Bruno
B
Clinica Neurologica, Azienda Ospedaliera of Verona, Verona, Italy. bruno.bonetti@univr.it
Valdo
Paola
P
Ossi
Giovanni
G
De Toni
Luca
L
Masotto
Barbara
B
Marconi
Silvia
S
Rizzuto
Nicolò
N
Nardelli
Ettore
E
Moretto
Giuseppe
G
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005434:Flow Cytometry / Q000295:instrumentation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism*; D019169:Jurkat Cells / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009464:Neuroma, Acoustic / Q000378:metabolism; D054353:Perforin; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating / Q000378:metabolism; D052899:Pore Forming Cytotoxic Proteins; D012583:Schwann Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma