CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells

Ashok Kumar; Troy D. Humphreys; Kimberly N. Kremer; Patricia S. Bramati; Lavone Bradfield; Contessa E. Edgar; Karen E. Hedin

doi:10.1016/j.immuni.2006.06.015

CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells

Ashok Kumar, Troy D. Humphreys, Kimberly N. Kremer, Patricia S. Bramati, Lavone Bradfield, Contessa E. Edgar, Karen E. Hedin

Immunology

Research output: Contribution to journal › Article › peer-review

172 Scopus citations

Abstract

SDF-1α (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1α-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1α stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1α on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1α costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1α and other chemokines on immunity.

Original language	English (US)
Pages (from-to)	213-224
Number of pages	12
Journal	Immunity
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2006.06.015
State	Published - Aug 2006

Keywords

MOLIMMUNO
SIGNALING

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2006.06.015

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title = "CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells",

abstract = "SDF-1α (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1α-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1α stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1α on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1α costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1α and other chemokines on immunity.",

keywords = "MOLIMMUNO, SIGNALING",

author = "Ashok Kumar and Humphreys, {Troy D.} and Kremer, {Kimberly N.} and Bramati, {Patricia S.} and Lavone Bradfield and Edgar, {Contessa E.} and Hedin, {Karen E.}",

note = "Funding Information: We thank A. Weiss, R. Abraham, and D. Billadeau for providing cells and reagents, J. Tarara and the Mayo Flow Cytometry Core Facility for expert technical assistance, and L. Pease, R. Bram, S. Kauffman, and P. Leibson for comments on the manuscript. This work was supported in part by the philanthropy of Barbara Lipps to the Mayo Clinic, by NIH Training Grants #AI074525 (to T.D.H.) and #GM55252 (to L.B.), and by NIH RO1 Grant #GM59763 (to K.E.H.). ",

year = "2006",

month = aug,

doi = "10.1016/j.immuni.2006.06.015",

language = "English (US)",

volume = "25",

pages = "213--224",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

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T1 - CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells

AU - Kumar, Ashok

AU - Humphreys, Troy D.

AU - Kremer, Kimberly N.

AU - Bramati, Patricia S.

AU - Bradfield, Lavone

AU - Edgar, Contessa E.

AU - Hedin, Karen E.

N1 - Funding Information: We thank A. Weiss, R. Abraham, and D. Billadeau for providing cells and reagents, J. Tarara and the Mayo Flow Cytometry Core Facility for expert technical assistance, and L. Pease, R. Bram, S. Kauffman, and P. Leibson for comments on the manuscript. This work was supported in part by the philanthropy of Barbara Lipps to the Mayo Clinic, by NIH Training Grants #AI074525 (to T.D.H.) and #GM55252 (to L.B.), and by NIH RO1 Grant #GM59763 (to K.E.H.).

PY - 2006/8

Y1 - 2006/8

N2 - SDF-1α (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1α-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1α stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1α on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1α costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1α and other chemokines on immunity.

AB - SDF-1α (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1α-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1α stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1α on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1α costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1α and other chemokines on immunity.

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KW - SIGNALING

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CXCR4 Physically Associates with the T Cell Receptor to Signal in T Cells

Abstract

Keywords

ASJC Scopus subject areas

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