期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 7, 页码 1425-1440出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20132687
关键词
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资金
- National Institutes of Health [AI042944, AI089624]
- Grants-in-Aid for Scientific Research [26257506, 25460592] Funding Source: KAKEN
Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fc gamma receptors in enabling the activity of CD40, TRAILR, and GITR when engaged by antibodies, other TNFR molecules may be controlled by additional mechanisms. Antibodies to 4-1BB (CD137) are currently in clinical trials and can both augment immunity in cancer and promote regulatory T cells that inhibit autoimmune disease. We found that the action of agonist anti-4-1BB in suppressing autoimmune and allergic inflammation was completely dependent on Galectin-9 (Gal-9). Gal-9 directly bound to 4-1BB, in a site distinct from the binding site of antibodies and the natural ligand of 4-1BB, and Gal-9 facilitated 4-1BB aggregation, signaling, and functional activity in T cells, dendritic cells, and natural killer cells. Conservation of the Gal-9 interaction in humans has important implications for effective clinical targeting of 4-1BB and possibly other TNFR superfamily molecules.
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