title: Stimulation of a shorter duration in the state of anergy by an invariant natural killer T cell agonist enhances its efficiency of protection from type 1 diabetes.
abstract: We have reported previously that treatment of non-obese diabetic (NOD) mice with the invariant natural killer T (iNK T) cell agonist α-galactosylceramide C26:0 (α-GalCer) or its T helper type 2 (Th2)-biasing derivative α-GalCer C20:2 (C20:2) protects against type 1 diabetes (T1D), with C20:2 yielding greater protection. After an initial response to α-GalCer, iNK T cells become anergic upon restimulation. While such anergic iNK T cells can induce tolerogenic dendritic cells (DCs) that mediate protection from T1D, chronic administration of α-GalCer also results in long-lasting anergy accompanied by significantly reduced iNK T cell frequencies, which raises concerns about its long-term therapeutic use. In this study, our objective was to understand more clearly the roles of anergy and induction of tolerogenic DCs in iNK T cell-mediated protection from T1D and to circumvent potential complications associated with α-GalCer. We demonstrate that NOD iNK T cells activated during multi-dose (MD) treatment in vivo with C20:2 enter into and exit from anergy more rapidly than after activation by α-GalCer. Importantly, this shorter duration of iNK T cells in the anergic state promotes the more rapid induction of tolerogenic DCs and reduced iNK T cell death, and enables C20:2 stimulated iNK T cells to elicit enhanced protection from T1D. Our findings further that suggest C20:2 is a more effective therapeutic drug than α-GalCer for protection from T1D. Moreover, the characteristics of C20:2 provide a basis of selection of next-generation iNK T cell agonists for the prevention of T1D.
authors.affiliation: Laboratory of Autoimmune Diabetes, Robarts Research Institute Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Tohn
authors.forename: H
authors.initials: H
authors.lastname: Blumenfeld
authors.forename: S M M
authors.initials: SM
authors.lastname: Haeryfar
authors.forename: N
authors.initials: N
authors.lastname: Veerapen
authors.forename: G S
authors.initials: GS
authors.lastname: Besra
authors.forename: S A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: T L
authors.initials: TL
authors.lastname: Delovitch
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000187:drug effects* / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D005699:Galactosylceramides; D008562:Membrane Glycoproteins; D010455:Peptides; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma