Ras/PI3kinase/cofilin-independent activation of human CD45RA+ and CD45RO+ T cells by superagonistic CD28 stimulation.
T cell activation requires costimulation of TCR/CD3 plus accessory receptors (e.g. CD28). A hallmark of costimulation is the dynamic reorganization of the actin cytoskeleton, important for receptor polarization in the immunological synapse. The classical model of T cell costimulation was challenged by the detection of superagonistic anti-CD28 antibodies. These induce T cell proliferation and--as demonstrated here--production of IFN-gamma, CD25 and CD69 even in the absence of TCR/CD3 coligation. Here, we analyzed whether superagonistic CD28 stimulation induces costimulatory signaling events. Costimulation leads to phosphorylation of the actin-bundling protein L-plastin and dephosphorylation of the actin-reorganizing protein cofilin. Cofilin binds to F-actin only in its dephosphorylated form. Binding of cofilin to F-actin leads to depolymerization or severing of F-actin. The latter ends up in smaller F-actin fragments, which can be elongated at the free barbed ends. This results in enhanced actin polymerization. Dephosphorylation of cofilin requires activation of Ras and PI3Kinase. Interestingly, superagonistic CD28 stimulation activates human peripheral blood T cells independently of Ras and PI3Kinase. Accordingly, it does not lead to cofilin dephosphorylation and receptor polarization. Likewise, L-plastin is not phosphorylated. Thus, superagonistic CD28 stimulation does not mimic costimulation. Instead, it leads to a Ras/PI3Kinase/cofilin-independent state of "unpolarized T cell activation".
Sester
Urban
U
Institute for Immunology, Ruprecht-Karls-University, Heidelberg, Germany.
Wabnitz
Guido H
GH
Kirchgessner
Henning
H
Samstag
Yvonne
Y
D051339:Actin Depolymerizing Factors / Q000502:physiology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism*; D016764:Cell Polarity / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology; D008934:Mitogens / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011817:Rabbits; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
D051339:Actin Depolymerizing Factors; D000906:Antibodies; D018106:CD28 Antigens; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D017493:Leukocyte Common Antigens; D018631:ras Proteins