The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites.
The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110gamma isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110gamma does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Naïve p110gamma(-/-) CD4 lymphocytes are phenotypically identical to their wild-type (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110gamma-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110gamma-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110gamma-deficient CD4 T cells express P-selectin ligand, beta2 integrin, beta1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired F-actin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110gamma regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.
Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Molly S
MS
Thomas
Jason S
JS
Mitchell
Christopher C
CC
DeNucci
Amanda L
AL
Martin
Yoji
Y
Shimizu
D000199:Actins / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000199:Actins; D018925:Chemokines; D011948:Receptors, Antigen, T-Cell; D019707:Receptors, Chemokine; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium