title: Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation.
abstract: Efficient adaptive immune responses require the localization of T lymphocytes in secondary lymphoid organs and inflamed tissues. To achieve correct localization of T lymphocytes, the migration of these cells is initiated and directed by adhesion molecules and chemokines. It has recently been shown that the inhibitory surface molecule CD152 (CTLA-4) initiates Th cell migration, but the molecular mechanism underlying this effect remains to be elucidated. Using CD4 T lymphocytes derived from OVA-specific TCR transgenic CD152-deficient and CD152-competent mice, we demonstrate that chemokine-triggered signal transduction is differentially regulated by CD152 via phosphoinositide 3-kinase (PI3K)-dependent activation of protein kinase B (PKB/Akt). In the presence of CD152 signaling, the chemoattractant CCL4 selectively induces the full activation of Akt via phosphorylation at threonine 308 and serine 473 in pro-inflammatory Th lymphocytes expressing the cognate chemokine receptor CCR5. Akt signals lead to cytoskeleton rearrangements, which are indispensable for migration. Therefore, this novel Akt-modulating function of CD152 signals affecting T cell migration demonstrates that boosting CD152 or its down-stream signal transduction could aid therapies aimed at sensitizing T lymphocytes for optimal migration, thus contributing to a precise and effective immune response.
authors.affiliation: Department of Experimental Pediatrics, University Hospital Magdeburg, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Knieke
authors.forename: Holger
authors.initials: H
authors.lastname: Lingel
authors.forename: Kathrin
authors.initials: K
authors.lastname: Chamaon
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054388:Receptors, CCR / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000201:enzymology* / Q000276:immunology*
chemical_list: D060908:CTLA-4 Antigen; D054388:Receptors, CCR; D019713:Receptors, CCR5; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt