title: A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats.
abstract: Administration of the CD28 superagonistic antibody JJ316 is an efficient means to treat autoimmune diseases in rats, but the humanized antibody TGN1412 caused devastating side effects in healthy volunteers during a clinical trial. Here we show that JJ316 treatment of rats induced a dramatic redistribution of T lymphocytes from the periphery to the secondary lymphoid organs, resulting in severe T lymphopenia. Live imaging of secondary lymphoid organs revealed that JJ316 administration almost instantaneously (<2 minutes) arrested T cells in situ. This reduction in T cell motility was accompanied by profound cytoskeletal rearrangements and increased cell size. In addition, surface expression of lymphocyte function-associated antigen-1 was enhanced, endothelial differentiation sphingolipid G protein-coupled receptor 1 and L selectin levels were downregulated, and the cells lost their responsiveness to sphingosine 1-phosphate-directed migration. These proadhesive alterations were accompanied by signs of strong activation, including upregulation of CD25, CD69, CD134, and proinflammatory mediators. However, this did not lead to a cytokine storm similar to the clinical trial. While most of the early changes disappeared within 48 hours, we observed that CD4+CD25+FoxP3+ regulatory T cells experienced a second phase of activation, which resulted in massive cell enlargement, extensive polarization, and increased motility. These data suggest that CD28 superagonists elicit 2 qualitatively distinct waves of activation.
authors: Institute for Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany.
authors: Nora
authors: N
authors: Müller
authors: Jens
authors: J
authors: van den Brandt
authors: Francesca
authors: F
authors: Odoardi
authors: Denise
authors: D
authors: Tischner
authors: Judith
authors: J
authors: Herath
authors: Alexander
authors: A
authors: Flügel
authors: Holger M
authors: HM
authors: Reichardt
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology*; D015415:Biomarkers; D018106:CD28 Antigens / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement; D016764:Cell Polarity / Q000276:immunology; D002470:Cell Survival; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003599:Cytoskeleton / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008221:Lymphoid Tissue / Q000276:immunology; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D015415:Biomarkers; D018106:CD28 Antigens; D016207:Cytokines