title: A motif in the V3 domain of the kinase PKC-θ determines its localization in the immunological synapse and functions in T cells via association with CD28.
abstract: Protein kinase C-θ (PKC-θ) translocates to the center of the immunological synapse, but the underlying mechanism and its importance in T cell activation are unknown. Here we found that the V3 domain of PKC-θ was necessary and sufficient for localization to the immunological synapse mediated by association with the coreceptor CD28 and dependent on the kinase Lck. We identified a conserved proline-rich motif in V3 required for association with CD28 and immunological synapse localization. We found association with CD28 to be essential for PKC-θ-mediated downstream signaling and the differentiation of T helper type 2 cells (T(H)2 cells) and interleukin 17-producing helper T cells (T(H)17 cells) but not of T helper type 1 cells (T(H)1 cells). Ectopic expression of V3 sequestered PKC-θ from the immunological synapse and interfered with its functions. Our results identify a unique mode of CD28 signaling, establish a molecular basis for the immunological synapse localization of PKC-θ and indicate V3-based 'decoys' may be therapeutic modalities for T cell-mediated inflammatory diseases.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Kok-Fai
authors.initials: KF
authors.lastname: Kong
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yokosuka
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Canonigo-Balancio
authors.forename: Noah
authors.initials: N
authors.lastname: Isakov
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054992:Immunological Synapses; D056747:Immunomodulation; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D055232:Proline-Rich Protein Domains / Q000235:genetics; D011485:Protein Binding / Q000276:immunology; D011493:Protein Kinase C / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D021381:Protein Transport / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D018106:CD28 Antigens; D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta