Structural and functional characterization of a novel nonglycosidic type I NKT agonist with immunomodulatory properties.
Activation of type I NKT (iNKT) cells by CD1d-presented agonists is a potent immunotherapeutic tool. α-Galactosylceramide (α-GalCer) is the prototypic agonist, but its excessive potency with simultaneous production of both pro- and anti-inflammatory cytokines hampers its potential therapeutic use. In search for novel agonists, we have analyzed the structure and function of HS44, a synthetic aminocyclitolic ceramide analog designed to avoid unrestrained iNKT cell activation. HS44 is a weaker agonist compared with α-GalCer in vitro, although in vivo it induces robust IFN-γ production, and highly reduced but still functional Th2 response. The characteristic cytokine storm produced upon α-GalCer activation was not induced. Consequently, HS44 induced a very efficient iNKT cell-dependent antitumoral response in B16 animal model. In addition, intranasal administration showed the capacity to induce lung inflammation and airway hyperreactivity, a cardinal asthma feature. Thus, HS44 is able to elicit functional Th1 or Th2 responses. Structural studies show that HS44 binds to CD1d with the same conformation as α-GalCer. The TCR binds to HS44 similarly as α-GalCer, but forms less contacts, thus explaining its weaker TCR affinity and, consequently, its weaker recognition by iNKT cells. The ability of this compound to activate an efficient, but not massive, tailored functional immune response makes it an attractive reagent for immune manipulation.
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Jerome
J
Kerzerho
Esther D
ED
Yu
Carolina M
CM
Barra
Elisenda
E
Alari-Pahissa
Elisenda
E
Alari-Pahisa
Enrico
E
Girardi
Youssef
Y
Harrak
Pilar
P
Lauzurica
Amadeu
A
Llebaria
Dirk M
DM
Zajonc
Omid
O
Akbari
A Raúl
AR
Castaño
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D054812:Cyclitols / Q000819:agonists / Q000737:chemistry* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000819:agonists / Q000737:chemistry* / Q000494:pharmacology*; D007155:Immunologic Factors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship
D054812:Cyclitols; D005699:Galactosylceramides; D007155:Immunologic Factors