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PMID: 20346707 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Immunity ·Vol. 32 ·No. 4 ·2010-04-23 ·Pages 541-56

Raab M, Wang H, Lu Y, Smith X, Wu Z, Strebhardt K, Ladbury JE, Rudd CE

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.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Apoptosis Regulatory Proteins Cell Adhesion Cell Movement Cells, Cultured Dendritic Cells/immunology Lymph Nodes/cytology,immunology,metabolism Lymphocyte Function-Associated Antigen-1/immunology,metabolism Mice Mice, Knockout Monomeric GTP-Binding Proteins/genetics,immunology,metabolism Mutation Phosphoproteins/deficiency,genetics,immunology,metabolism Protein Binding Protein Transport Receptors, Antigen, T-Cell/immunology,metabolism Signal Transduction T-Lymphocytes/cytology,immunology,metabolism rap1 GTP-Binding Proteins/immunology,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins 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
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Raab Monika
Cell Signaling Section, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge UK, CB2 1Q.
Wang Hongyan
Lu Yuning
Smith Xin
Wu Zhonglin
Strebhardt Klaus
Ladbury John E
Rudd Christopher E
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2010.03.007
Published
2010-04-23
Epub
2010-00-25
Pages
541-56
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC3812847
Subset
IM
Grants
Wellcome Trust · 092627 · United Kingdom
External Links
PubMed source DOI: 10.1016/j.immuni.2010.03.007 PMC Full Text View journal details
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