Examining the role of CD1d and natural killer T cells in the development of nephritis in a genetically susceptible lupus model.
Arthritis Rheum
; 56(4): 1219-33, 2007 Apr.
Article
em En
| MEDLINE
| ID: mdl-17393451
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.CONCLUSION:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nefrite Lúpica
/
Células Matadoras Naturais
/
Linfócitos T
/
Antígenos CD1
/
Predisposição Genética para Doença
/
Lúpus Eritematoso Sistêmico
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Arthritis Rheum
Ano de publicação:
2007
Tipo de documento:
Article