title: Cooperation of invariant NKT cells and CD4+CD25+ T regulatory cells in the prevention of autoimmune myasthenia.
abstract: CD1d-restricted NKT cells and CD4+CD25+ regulatory T (Treg) cells are thymus-derived subsets of regulatory T cells that have an important role in the maintenance of self-tolerance. Whether NKT cells and Treg cells cooperate functionally in the regulation of autoimmunity is not known. We have explored this possibility in experimental autoimmune myasthenia gravis (EAMG), an animal model of human myasthenia gravis, induced by immunization of C57BL/6 mice with the autoantigen acetylcholine receptor. We have demonstrated that activation of NKT cells by a synthetic glycolipid agonist of NKT cells, alpha-galactosylceramide (alpha-GalCer), inhibits the development of EAMG. alpha-GalCer administration in EAMG mice increased the size of the Treg cell compartment, and augmented the expression of foxp3 and the potency of CD4+CD25+ cells to inhibit proliferation of autoreactive T cells. Furthermore, alpha-GalCer promoted NKT cells to transcribe the IL-2 gene and produce IL-2 protein. Depletion of CD25+ cells or neutralization of IL-2 reduced the therapeutic effect of alpha-GalCer in this model. Thus, alpha-GalCer-activated NKT cells can induce expansion of CD4+CD25+ Treg cells, which in turn mediate the therapeutic effects of alpha-GalCer in EAMG. Induced cooperation of NKT cells and Treg cells may serve as a superior strategy to treat autoimmune disease.
authors.affiliation: Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Liu
authors.forename: Antonio
authors.initials: A
authors.lastname: La Cava
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
authors.forename: Youngheun
authors.initials: Y
authors.lastname: Jee
authors.forename: Mary
authors.initials: M
authors.lastname: Price
authors.forename: Denise I
authors.initials: DI
authors.lastname: Campagnolo
authors.forename: Premkumar
authors.initials: P
authors.lastname: Christadoss
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Vollmer
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Fu-Dong
authors.initials: FD
authors.lastname: Shi
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005699:Galactosylceramides / Q000494:pharmacology* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D015375:Receptors, Interleukin-2; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005699:Galactosylceramides; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; C493154:alpha-galactosylceramide