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- Title
TMEM16F mediates bystander TCR-CD3 membrane dissociation at the immunological synapse and potentiates T cell activation.
- Authors
Connolly, Audrey; Panes, Rébecca; Tual, Margaux; Lafortune, Raphaël; Bellemare-Pelletier, Angélique; Gagnon, Etienne
- Abstract
Flipping the switch in T cells: The cytoplasmic domains of some of the CD3 subunits within the T cell receptor (TCR) complex localize along the inner leaflet of the plasma membrane through electrostatic interactions, thereby inhibiting their phosphorylation and activation. Connolly et al. found that the scramblase TMEM16F, which redistributes phosphatidylserine from the inner to the outer leaflet of the plasma membrane, enabled CD3 cytoplasmic domains of bystander TCRs to disengage from the plasma membrane, leading to enhanced T cell activation. These bystander TCRs were in the vicinity of antigen-stimulated TCRs and served to amplify T cell signaling. Thus, targeting TMEM16F therapeutically may enable modulation of T cell activation. Electrostatic interactions regulate many aspects of T cell receptor (TCR) activity, including enabling the dynamic binding of the TCR-associated CD3ε and CD3ζ chains to anionic lipids in the plasma membrane to prevent spontaneous phosphorylation. Substantial changes in the electrostatic potential of the plasma membrane occur at the immunological synapse, the interface between a T cell and an antigen-presenting cell. Here, we investigated how the electrostatic interactions that promote dynamic membrane binding of the TCR-CD3 cytoplasmic domains are modulated during signaling and affect T cell activation. We found that Ca2+-dependent activation of the phosphatidylserine scramblase TMEM16F, which was previously implicated in T cell activation, reduced the electrostatic potential of the plasma membrane during immunological synapse formation by locally redistributing phosphatidylserine. This, in turn, increased the dissociation of bystander TCR-CD3 cytoplasmic domains from the plasma membrane and enhanced TCR-dependent signaling and consequently T cell activation. This study establishes the molecular basis for the role of TMEM16F in bystander TCR–induced signal amplification and identifies enhancement of TMEM16F function as a potential therapeutic strategy for promoting T cell activation.
- Subjects
T cell receptors; ELECTRIC potential; ELECTROSTATIC interaction; SYNAPTOGENESIS; BLOOD lipids; ANTIGEN presenting cells
- Publication
Science Signaling, 2021, Vol 14, Issue 675, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abb5146