SLAT promotes TCR-mediated, Rap1-dependent LFA-1 activation and adhesion through interaction of its PH domain with Rap1

Marjorie Côte, Camille Fos, Ann J. Canonigo-Balancio, Klaus Ley, Stéphane Bécart, Amnon Altman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

SLAT (also known as DEF6) promotes T cell activation and differentiation by regulating NFAT-Ca2+ signaling. However, its role in TCR-mediated inside-out signaling, which induces integrin activation and T cell adhesion, a central process in T cell immunity and inflammation, has not been explored. Here, we show that SLAT is crucial for TCR-induced adhesion to ICAM-1 and affinity maturation of LFA-1 in CD4+ T cells. Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4+ T cell adhesion. Finally, we established that a constitutively active form of Rap1, which is present at the plasma membrane, rescues the defective LFA-1 activation and ICAM-1 adhesion in SLAT-deficient (Def6-/-) T cells. These findings ascribe a new function to SLAT, and identify Rap1 as a target of SLAT function in TCR-mediated inside-out signaling.

Original languageEnglish (US)
Pages (from-to)4341-4352
Number of pages12
JournalJournal of Cell Science
Volume128
Issue number23
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Def6
  • Immunological synapse
  • Inside-out signaling
  • Integrin activation
  • Rap1
  • SLAT
  • T cell-adhesion

ASJC Scopus subject areas

  • Cell Biology

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