Fas signalling promotes intercellular communication in T cells

PLoS One. 2012;7(4):e35766. doi: 10.1371/journal.pone.0035766. Epub 2012 Apr 25.

Abstract

Cell-to-cell communication is a fundamental process for development and maintenance of multicellular organisms. Diverse mechanisms for the exchange of molecular information between cells have been documented, such as the exchange of membrane fragments (trogocytosis), formation of tunneling nanotubes (TNTs) and release of microvesicles (MVs). In this study we assign to Fas signalling a pivotal role for intercellular communication in CD4+ T cells. Binding of membrane-bound FasL to Fas expressing target cells triggers a well-characterized pro-apoptotic signalling cascade. However, our results, pairing up flow cytometric studies with confocal microscopy data, highlight a new social dimension for Fas/FasL interactions between CD4+ T cells. Indeed, FasL enhances the formation of cell conjugates (8 fold of increase) in an early time-frame of stimulation (30 min), and this phenomenon appears to be a crucial step to prime intercellular communication. Our findings show that this communication mainly proceeds along a cytosolic material exchange (ratio of exchange >10, calculated as ratio of stimulated cells signal divided by that recorded in control cells) via TNTs and MVs release. In particular, inhibition of TNTs genesis by pharmacological agents (Latruculin A and Nocodazole) markedly reduced this exchange (inhibition percentage: >40% and >50% respectively), suggesting a key role for TNTs in CD4+ T cells communication. Although MVs are present in supernatants from PHA-activated T cells, Fas treatment also leads to a significant increase in the amount of released MVs. In fact, the co-culture performed between MVs and untreated cells highlights a higher presence of MVs in the medium (1.4 fold of increase) and a significant MVs uptake (6 fold of increase) by untreated T lymphocytes. We conclude that Fas signalling induces intercellular communication in CD4+ T cells by different mechanisms that seem to start concomitantly with the main pathway (programmed cell death) promoted by FasL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Biological Transport / drug effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Communication / drug effects
  • Cell Communication / physiology*
  • Cells, Cultured
  • Cytoplasmic Vesicles / metabolism
  • Fas Ligand Protein / metabolism*
  • Flow Cytometry
  • Humans
  • Lymphocyte Activation / drug effects
  • Nocodazole / pharmacology
  • Phytohemagglutinins / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Thiazolidines / pharmacology
  • fas Receptor / metabolism*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • FAS protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • Phytohemagglutinins
  • Thiazolidines
  • fas Receptor
  • Nocodazole
  • latrunculin A