title: Proliferative signals mediated by CD28 superagonists require the exchange factor Vav1 but not phosphoinositide 3-kinase in primary peripheral T cells.
abstract: Almost all responses of naive T cells require co-stimulation, i.e. engagement of the clonotypic TCR with relevant antigen/MHC and the co-stimulatory molecule CD28. How CD28 contributes to T-cell proliferation remains poorly understood, with widely conflicting reports existing which may reflect different methods of co-ligating receptors. Some CD28 mAb, however, can stimulate T-cell proliferation without the need for TCR co-ligation, and thus provide unique tools to dissect proliferative signals mediated through CD28 alone. Using primary peripheral T cells from CD28-transgenic mice, we show that both the YMNM and Lck-binding motifs, but not the Itk-binding motif, in CD28 are required for proliferation. Given that the YMNM motif recruits both phosphoinositide 3-kinase (PI3K) and the exchange factor Vav1, we investigated the role of these two molecules in CD28-mediated proliferation. In p110delta(D910A/D910A) transgenic T cells, which are defective in PI3K activation following CD28 ligation, proliferation was comparable to that in wild-type cells. By contrast, T-cell proliferation was abolished in Vav1(-/-) cells. Although we did not address the role of Grb2 in CD28 signalling, these results indicate that CD28 can mediate Lck- and Vav1-dependent proliferative signals independently of PI3K.
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors.forename: Tea
authors.initials: T
authors.lastname: Gogishvili
authors.forename: Fernando
authors.initials: F
authors.lastname: Elias
authors.forename: Juliet L
authors.initials: JL
authors.lastname: Emery
authors.forename: Kirsty
authors.initials: K
authors.lastname: McPherson
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Dennehy
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D018106:CD28 Antigens / Q000737:chemistry / Q000276:immunology*; D049109:Cell Proliferation; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D019870:1-Phosphatidylinositol 4-Kinase