title: Co-engagement of alpha(4)beta(1) integrin (VLA-4) and CD4 or CD8 is necessary to induce maximal Erk1/2 phosphorylation and cytokine production in human T cells.
abstract: The alpha(4)beta(1) integrin VLA-4 (very-late activation antigen-4) and the lineage-specific CD4 and CD8 receptors have been proposed as putative co-stimulatory receptors on T cells. To assess the relative contribution of signaling through the TCR, CD28 and these accessory molecules, we activated human T cells using soluble antibodies recognizing all four of these T-cell receptor classes (CD3, CD28, CD4/CD8, and VLA-4), and we assessed the degree of activation using higher-order flow cytometry detecting intracellular Erk1/2 phosphorylation and production of IL-2 and IFN-gamma. We found that: (1) co-stimulation via CD4/CD8, in addition to CD28, is required for optimal T-cell activation; (2) VLA-4 binding consistently potentiates CD4(+) and CD8(+) T-cell activation; (3) augmentation of T-cell activation through VLA-4 binding is most pronounced following engagement of CD4/CD8. These results confirm that multiple signals, including VLA-4 engagement, are necessary for maximal T-cell activation beyond that induced via the TCR and CD28.
authors.affiliation: Adult Stem Cell Transplant Program, University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
authors.forename: Tae Kon
authors.initials: TK
authors.lastname: Kim
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Billard
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieder
authors.forename: Bradley W
authors.initials: BW
authors.lastname: McIntyre
authors.forename: Krishna V
authors.initials: KV
authors.lastname: Komanduri
mesh_terms: D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D039041:Integrin alpha4beta1 / Q000276:immunology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D039041:Integrin alpha4beta1; D011948:Receptors, Antigen, T-Cell; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3