A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats
2008 | journal article. A publication with affiliation to the University of Göttingen.
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A CD28 superagonistic antibody elicits 2 functionally distinct waves of T cell activation in rats
Mueller, N.; van den Brandt, J.; Odoardi, F. ; Tischner, D.; Herath, J.; Fluegel, A. & Reichardt, H. M. (2008)
Journal of Clinical Investigation, 118(4) pp. 1405-1416. DOI: https://doi.org/10.1172/JCI32698
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- Authors
- Mueller, Nora; van den Brandt, Jens; Odoardi, Francesca ; Tischner, Denise; Herath, Judith; Fluegel, Alexander; Reichardt, Holger Michael
- 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.
- Issue Date
- 2008
- Status
- published
- Publisher
- Amer Soc Clinical Investigation Inc
- Journal
- Journal of Clinical Investigation
- ISSN
- 0021-9738