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

Ruggero De Maria, Monica Boirivant, Maria Grazia Cifone, Paola Roncaioli, Michael Hahne, Jurg Tschopp, Francesco Pallone, Angela Santoni, Roberto Testi

Research output: Contribution to journalArticlepeer-review

Abstract

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 pregress 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.

Original languageEnglish
Pages (from-to)316-322
Number of pages7
JournalJournal of Clinical Investigation
Volume97
Issue number2
Publication statusPublished - Jan 15 1996

Keywords

  • Acidic sphingomyelinase
  • CD95
  • Fas/APO-1
  • Gut mucosa
  • T-LPL

ASJC Scopus subject areas

  • Medicine(all)

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