Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation.
The expression and function of Fas (CD95/APO-1), a cell surface receptor directly responsible for triggering cell death by apoptosis, was investigated on human T lymphocytes resident within the intestinal lamina propria, a major site of antigen challenge and persistent lymphocyte activation. Three color immunofluorescence and FACS analysis indicated that virtually all freshly isolated human gut lamina propria T lymphocytes (T-LPL) express Fas, together with the marker of progress activation CD45R0. A discrete fraction of freshly isolated T-LPL also constitutively expressed Fas ligand (FasL), perhaps as a result of recent in vivo activation. Importantly, whereas Fas cross-linking did not result in apoptosis induction in peripheral blood T lymphocytes (T-PBL), Fas was found to be fully effective in generating the apoptotic signal in T-LPL. This was associated with the activation of an acidic sphingomyelinase and with ceramide generation, early events known to be involved in Fas-mediated apoptotic signaling. By contrast, acidic sphingomyelinase activation and ceramide production were not detectable in T-PBL after Fas cross-linking. However C2-ceramide, a cell permeant synthetic analog of ceramide, could efficiently induce apoptosis in T-LPL and T-PBL when added exogenously. These data indicate that T-LPL constitutively express both Fas and FasL and that Fas cross-linking generates signals resulting in sphingomyelin hydrolysis and apoptosis, outlining a potential mechanism involved in intestinal tolerance. Moreover, they provide the first evidence of a role for ceramide-mediated pathways in normal immunoregulation.
De Maria
R
R
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
Boirivant
M
M
Cifone
M G
MG
Roncaioli
P
P
Hahne
M
M
Tschopp
J
J
Pallone
F
F
Santoni
A
A
Testi
R
R
D017209:Apoptosis; D002518:Ceramides / Q000494:pharmacology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D013109:Sphingomyelins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D002518:Ceramides; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D013109:Sphingomyelins; D019014:fas Receptor; D017493:Leukocyte Common Antigens; D013108:Sphingomyelin Phosphodiesterase