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.
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.
Kim
Tae Kon
TK
Adult Stem Cell Transplant Program, University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
Billard
Matthew J
MJ
Wieder
Eric D
ED
McIntyre
Bradley W
BW
Komanduri
Krishna V
KV
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
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