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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 15, 2009 |
| Title |
Differential gene expression in wild-type versus Yaa mutant mouse spleen cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
T cells from many patients with systemic lupus erythematosus are hypoproliferative in response to TCR ligation. This defect is mediated, at least in part, through down regulation of the TCR zeta chain. Investigation of this phenomenon in lupus-prone mice revealed that the hypoproliferative T cell phenotype apparent in BXSB males is mediated
in part by the Yaa locus. The BXSB model of lupus is a recombinant inbred strain that was originally derived from a cross between a male SB/LE mouse and a female C57BL/6 mouse. BXSB is unique among lupus-prone mouse strains, in that males carry an autoimmune accelerating factor on the Y chromosome, termed Yaa, which accelerates disease onset in male BXSB mice so that fatal glomerulonephritis occurs around 6 months of age. It was recently reported that the Yaa locus is a translocation of a short stretch of genes including that encoding Toll-like
receptor 7 (Tlr-7) from the X to the Y chromosome, leading to a two-fold over expression of a subset of these genes, including Tlr-7, and hypersensitivity of Yaa+ cells to TLR-7 agonists.
To more fully understand the functional significance of the Yaa gene and how it plays a part in the modulation of CD4+ T cell responses, we performed microarray analysis using Affymetrix 430 2.0 arrays on spleens from B6 male B6.Yaa male samples. The analysis revealed an enhanced signature of innate immunity, including increased expression not only of Tlr7 and Tlr8, in line with reports that the Yaa locus leads to a duplication of the murine Tlr7 and Tlr8 genes , but also of Tlr2, Tlr5, Cd14, Lbp, C2, C3 and genes for several heat-shock proteins. T cells from B6.Yaa mice also displayed decreased TCRζ expression. Interestingly, cell surface levels of the inhibitory molecule B7-H1 were increased on B6.Yaa B cells and monocytes/macrophages. In line with increased TLR-7 expression reported in B6.Yaa mice, the TLR-7 agonist imiquimod increased B7-H1 expression on normal B cells. Restoration of proliferation in co-cultures of B6 T cells and B6.Yaa APC with B7-H1 blocking Ab demonstrated a mechanistic contribution of B7-H1 up-regulation to Yaa-mediated APC-dependent T cell hypoproliferation. In addition, T cell hypoproliferation was induced in normal B6 T cells in vitro by the application of imiquimod. However, this defect was not mediated by B7-H1 or secreted factors but was independent of APC and mediated through direct imiquimod stimulation of T cells themselves. We postulate that excessive TLR-7 stimulation in Yaa+ mice mediates T cell hypoproliferation in part through up-regulation of B7-H1 and possibly also through direct T cell-mediated effects.
Keywords: differential gene expression, RNA, spleen, C57Bl/6J, B6.SB-Yaa/J, male, wild type, Yaa
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| Overall design |
Control mice: four C57Bl/6J male spleens
Experimental mice: three B6.SB-Yaa/J male spleens and one pool of two B6.Yaa male spleens for the third Yaa sample (GSM236622)
All mice were obtained from the Jackson Laboratories between March and December 2005.
Spleen cell suspensions were prepared by teasing spleen tissue through 70 micron nylon screens and lysing red cells with ammonium chloride.
All mice were 8 weeks of age at the time of the experiment.
RNA was separately extracted, labeled, and hybridized from each animal.
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| Contributor(s) |
Mudd PA, Teague BN, Frank MB, Dozmorov IM, Cadwell RC, Deen M, Rodgers W, Centola M, Farris D |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Oct 10, 2007 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Bart Frank |
| E-mail(s) |
frank@omrf.org
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| Organization name |
OMRF
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| Street address |
825 NE 13 St
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| City |
Oklahoma City |
| State/province |
OK |
| ZIP/Postal code |
73103 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA102923 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE9287_RAW.tar |
31.3 Mb |
(http)(custom) |
TAR (of CEL, CHP) |
| Processed data included within Sample table |
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