title: Examining the role of CD1d and natural killer T cells in the development of nephritis in a genetically susceptible lupus model.
abstract: OBJECTIVE
  CD1d-reactive invariant natural killer T (iNKT) cells secrete multiple cytokines upon T cell receptor (TCR) engagement and modulate many immune-mediated conditions. The purpose of this study was to examine the role of these cells in the development of autoimmune disease in genetically lupus-prone (NZBxNZW)F1 (BWF1) mice.
  
  
  METHODS
  The CD1d1-null genotype was crossed onto the NZB and NZW backgrounds to establish CD1d1-knockout (CD1d0) BWF1 mice. CD1d0 mice and their wild-type littermates were monitored for the development of nephritis and assessed for cytokine responses to CD1d-restricted glycolipid alpha-galactosylceramide (alphaGalCer), anti-CD3 antibody, and concanavalin A (Con A). Thymus and spleen cells were stained with CD1d tetramers that had been loaded with alphaGalCer or its analog PBS-57 to detect iNKT cells, and the cells were compared between BWF1 mice and class II major histocompatibility complex-matched nonautoimmune strains, including BALB/c, (BALB/cxNZW)F1 (CWF1), and NZW.
  
  
  RESULTS
  CD1d0 BWF1 mice had more severe nephritis than did their wild-type littermates. Although iNKT cells and iNKT cell responses were absent in CD1d0 BWF1 mice, the CD1d0 mice continued to have significant numbers of interferon-gamma-producing NKT-like (CD1d-independent TCRbeta+,NK1.1+ and/or DX5+) cells. CD1d deficiency also influenced cytokine responses by conventional T cells: upon in vitro stimulation of splenocytes with Con A or anti-CD3, type 2 cytokine levels were reduced, whereas type 1 cytokine levels were increased or unchanged in CD1d0 mice as compared with their wild-type littermates. Additionally, numbers of thymic iNKT cells were lower in young wild-type BWF1 mice than in nonautoimmune strains.
  
  
  CONCLUSIONS
  Germline deletion of CD1d exacerbates lupus in BWF1 mice. This finding, together with reduced thymic iNKT cells in young BWF1 mice as compared with nonautoimmune strains, implies a regulatory role of CD1d and iNKT cells during the development of lupus.
authors: University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors: Jun-Qi
authors: JQ
authors: Yang
authors: Xiangshu
authors: X
authors: Wen
authors: Hongzhu
authors: H
authors: Liu
authors: Gbolahan
authors: G
authors: Folayan
authors: Xin
authors: X
authors: Dong
authors: Min
authors: M
authors: Zhou
authors: Luc
authors: L
authors: Van Kaer
authors: Ram Raj
authors: RR
authors: Singh
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000276:immunology*; D055610:Antigens, CD1d; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000494:pharmacology; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; C512575:PBS 57; D007371:Interferon-gamma