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1-3 of 3
Dirk M. Zajonc
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Journal Articles
Shravan Madireddi, So-Young Eun, Seung-Woo Lee, Ivana Nemčovičová, Amit Kumar Mehta, Dirk M. Zajonc, Nozomu Nishi, Toshiro Niki, Mitsuomi Hirashima, Michael Croft
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2014) 211 (7): 1433–1448.
Published: 23 June 2014
Abstract
Biologics to TNF family receptors are prime candidates for therapy of immune disease. Whereas recent studies have highlighted a requirement for Fcγ 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.
Includes: Supplementary data
Journal Articles
Yali Li, Enrico Girardi, Jing Wang, Esther Dawen Yu, Gavin F. Painter, Mitchell Kronenberg, Dirk M. Zajonc
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2010) 207 (11): 2383–2393.
Published: 04 October 2010
Abstract
Invariant natural killer T cells (iNKT cells) rapidly produce effector cytokines. In this study, we report the first crystal structures of the iNKT cell T cell receptor (TCR) bound to two natural, microbial glycolipids presented by CD1d. Binding of the TCR induced CDR3-α–dependent structural changes in the F′ roof of CD1d; these changes resemble those occurring in the absence of TCR engagement when the highly potent synthetic antigen α-galactosylceramide (α-GalCer) binds CD1d. Furthermore, in the Borrelia burgdorferi α–galactosyl diacylglycerol–CD1d complex, TCR binding caused a marked repositioning of the galactose sugar into an orientation that closely resembles α-GalCer. The TCR-dependent reorientation of the sugar, together with the induced CD1d fit, may explain the weaker potency of the microbial antigens compared with α-GalCer. We propose that the TCR of iNKT cells binds with a conserved footprint onto CD1d, regardless of the bound glycolipid antigen, and that for microbial antigens this unique binding mode requires TCR-initiated conformational changes.
Includes: Supplementary data
Journal Articles
Dirk M. Zajonc, Igor Maricic, Douglass Wu, Ramesh Halder, Keshab Roy, Chi-Huey Wong, Vipin Kumar, Ian A. Wilson
Journal:
Journal of Experimental Medicine
Journal of Experimental Medicine (2005) 202 (11): 1517–1526.
Published: 28 November 2005
Abstract
Sulfatide derived from the myelin stimulates a distinct population of CD1d-restricted natural killer T (NKT) cells. Cis-tetracosenoyl sulfatide is one of the immunodominant species in myelin as identified by proliferation, cytokine secretion, and CD1d tetramer staining. The crystal structure of mouse CD1d in complex with cis-tetracosenoyl sulfatide at 1.9 Å resolution reveals that the longer cis-tetracosenoyl fatty acid chain fully occupies the A ′ pocket of the CD1d binding groove, whereas the sphingosine chain fills up the F ′ pocket. A precise hydrogen bond network in the center of the binding groove orients and positions the ceramide backbone for insertion of the lipid tails in their respective pockets. The 3 ′ -sulfated galactose headgroup is highly exposed for presentation to the T cell receptor and projects up and away from the binding pocket due to its β linkage, compared with the more intimate binding of the α -glactosyl ceramide headgroup to CD1d. These structure and binding data on sulfatide presentation by CD1d have important implications for the design of therapeutics that target T cells reactive for myelin glycolipids in autoimmune diseases of the central nervous system.