The p110γ isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites

Molly S. Thomas, Jason S Mitchell, Christopher C. Denucci, Amanda L. Martin, Yoji Shimizu

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110γ isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110γ does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Naïve p110γ-/- CD4 lymphocytes are phenotypically identical to their wildtype (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110γ-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110γ-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110γ-deficient CD4 T cells express P-selectin ligand, β2 integrin, β1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired Factin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110γ regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.

Original languageEnglish (US)
Pages (from-to)814-823
Number of pages10
JournalJournal of Leukocyte Biology
Volume84
Issue number3
DOIs
StatePublished - Sep 1 2008

Fingerprint

Phosphatidylinositol 3-Kinase
Protein Isoforms
T-Lymphocytes
Antigens
Phosphatidylinositol 3-Kinases
Integrins
Lymphocytes
Ligands
CD4 Antigens
P-Selectin
Adaptive Immunity
Cell Movement
Leukocytes
Cell Proliferation
Calcium

Keywords

  • Activation
  • Chemokines
  • Inflammation
  • Leukocyte
  • Trafficking

Cite this

The p110γ isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites. / Thomas, Molly S.; Mitchell, Jason S; Denucci, Christopher C.; Martin, Amanda L.; Shimizu, Yoji.

In: Journal of Leukocyte Biology, Vol. 84, No. 3, 01.09.2008, p. 814-823.

Research output: Contribution to journalArticle

@article{7e6d1c6aea4049bd998a6889ce360104,
title = "The p110γ isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites",
abstract = "The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110γ isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110γ does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Na{\"i}ve p110γ-/- CD4 lymphocytes are phenotypically identical to their wildtype (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110γ-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110γ-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110γ-deficient CD4 T cells express P-selectin ligand, β2 integrin, β1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired Factin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110γ regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.",
keywords = "Activation, Chemokines, Inflammation, Leukocyte, Trafficking",
author = "Thomas, {Molly S.} and Mitchell, {Jason S} and Denucci, {Christopher C.} and Martin, {Amanda L.} and Yoji Shimizu",
year = "2008",
month = "9",
day = "1",
doi = "10.1189/jlb.0807561",
language = "English (US)",
volume = "84",
pages = "814--823",
journal = "Journal of Leukocyte Biology",
issn = "0741-5400",
publisher = "FASEB",
number = "3",

}

TY - JOUR

T1 - The p110γ isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites

AU - Thomas, Molly S.

AU - Mitchell, Jason S

AU - Denucci, Christopher C.

AU - Martin, Amanda L.

AU - Shimizu, Yoji

PY - 2008/9/1

Y1 - 2008/9/1

N2 - The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110γ isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110γ does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Naïve p110γ-/- CD4 lymphocytes are phenotypically identical to their wildtype (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110γ-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110γ-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110γ-deficient CD4 T cells express P-selectin ligand, β2 integrin, β1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired Factin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110γ regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.

AB - The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110γ isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110γ does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Naïve p110γ-/- CD4 lymphocytes are phenotypically identical to their wildtype (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110γ-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110γ-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110γ-deficient CD4 T cells express P-selectin ligand, β2 integrin, β1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired Factin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110γ regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.

KW - Activation

KW - Chemokines

KW - Inflammation

KW - Leukocyte

KW - Trafficking

UR - http://www.scopus.com/inward/record.url?scp=50849122062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50849122062&partnerID=8YFLogxK

U2 - 10.1189/jlb.0807561

DO - 10.1189/jlb.0807561

M3 - Article

C2 - 18523230

AN - SCOPUS:50849122062

VL - 84

SP - 814

EP - 823

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

IS - 3

ER -