T cell receptor "inside-out" pathway via signaling module SKAP1-RapL regulates T cell motility and interactions in lymph nodes

Immunity. 2010 Apr 23;32(4):541-56. doi: 10.1016/j.immuni.2010.03.007. Epub 2010 Mar 25.

Abstract

Although essential for T cell function, the identity of the T cell receptor "inside-out" pathway for lymphocyte function-associated antigen 1 (LFA-1) adhesion has proved elusive. Here, we define the "inside-out" pathway mediated by N-terminal SKAP1 (SKAP-55) domain binding to the C-terminal SARAH domain of RapL. TcR induced Rap1-RapL complex formation and LFA-1 binding failed to occur in Skap1(-/-) primary T cells. SKAP1 generated a SKAP1-RapL-Rap1 complex that bound to LFA-1, whereas a RapL mutation (L224A) that abrogated SKAP1 binding without affecting MST1 disrupted component colocalization in vesicles as well as T cell-dendritic cell (DC) conjugation. RapL expression also "slowed" T cell motility in D011.10 transgenic T cells in lymph nodes (LNs), an effect reversed by the L224A mutation with reduced dwell times between T cells and DCs. Overall, our findings define a TCR "inside-out" pathway via N-SKAP1-C-RapL that regulates T cell adhesion, motility, and arrest times with DCs in LNs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Movement
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Lymph Nodes / cytology
  • Lymph Nodes / immunology*
  • Lymph Nodes / metabolism
  • Lymphocyte Function-Associated Antigen-1 / immunology
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice
  • Mice, Knockout
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / immunology
  • Monomeric GTP-Binding Proteins / metabolism*
  • Mutation
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / immunology*
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Protein Transport
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • rap1 GTP-Binding Proteins / immunology
  • rap1 GTP-Binding Proteins / metabolism*

Substances

  • Lymphocyte Function-Associated Antigen-1
  • Phosphoproteins
  • RAPL protein, mouse
  • RASSF5 protein, human
  • Receptors, Antigen, T-Cell
  • SKAP1 protein, human
  • SKAP1 protein, mouse
  • Monomeric GTP-Binding Proteins
  • rap1 GTP-Binding Proteins