Migration of Th1 lymphocytes is regulated by CD152 (CTLA-4)-mediated signaling via PI3 kinase-dependent Akt activation

• Published in: PloS one Vol. 7; no. 3; p. e31391
• Main Authors: Knieke, Karin, Lingel, Holger, Chamaon, Kathrin, Brunner-Weinzierl, Monika C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.03.2012; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptive immunity; AKT protein; Animal tissues; Animals; Biology; Carbon tetrachloride; CCL4 protein; CCR5 protein; CD152 antigen; CD4 antigen; Cell activation; Cell adhesion & migration; Cell adhesion molecules; Cell cycle; Cellular signal transduction; Chemokine receptors; Chemokines; Chemotactic factors; Chemotaxis, Leukocyte - immunology; CTLA-4 Antigen - genetics; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytoskeleton; Enzyme Activation - genetics; Genetic engineering; Helper cells; Immune response; Immune system; Inflammation; Kinases; Leukocyte migration; Ligands; Localization; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Organs; Phosphatase; Phosphatidylinositol 3-Kinases - metabolism; phosphoinositides; Phosphorylation; Protein kinases; Proteins; Proteomics; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CCR - metabolism; Receptors, CCR5 - metabolism; Rodents; Sensitizing; Serine; Signal Transduction; Signaling; T cell receptors; T cells; T-cell receptor; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Th1 Cells - enzymology; Th1 Cells - immunology; Threonine; Transgenic mice; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0031391

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.