Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function

Gregory J. Berry, Christine Frielle, Thaiphi Luu, Anna C. Salzberg, Daniel B. Rainbow, Linda S. Wicker, Hanspeter Waldner

Research output: Contribution to journalArticle

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Abstract

Type 1 diabetes (T1D) is a polygenic disease with multiple insulin-dependent diabetes (Idd) loci predisposing humans and NOD mice to disease. NOD.B10 Idd9 congenic mice, in which the NOD Idd9 chromosomal region is replaced by the Idd9 from T1D-resistant C57BL/10 mice, are significantly protected from T1D development. However, the genes and pathways conferring T1D development or protection by Idd9 remain to be fully elucidated. We have developed novel NOD.B10-Idd9 (line 905) congenic mice that predominantly harbor islet-reactive CD4+ T cells expressing the BDC2.5 TCR (BDC-Idd9.905 mice). To establish functional links between the Idd9 genotype and its phenotype, we used microarray analyses to investigate the gene expression profiles of ex vivo and Ag-activated CD4+ T cells from these mice and BDC2.5 (BDC) NOD controls. Among the differentially expressed genes, those located within the Idd9 region were greatly enriched in islet-specific CD4+ T cells. Bioinformatics analyses of differentially expressed genes between BDC-Idd9.905 and BDC CD4+ T cells identified Eno1, Rbbp4, and Mtor, all of which are encoded by Idd9 and part of gene networks involved in cellular growth and development. As predicted, proliferation and Th1/Th17 responses of islet-specific CD4+ T cells from BDC-Idd9.905 mice following Ag stimulation in vitro were reduced compared with BDC mice. Furthermore, proliferative responses to endogenous autoantigen and diabetogenic function were impaired in BDC-Idd9.905 CD4+ T cells. These findings suggest that differential expression of the identified Idd9 genes contributed to Idd9-dependent T1D susceptibility by controlling the diabetogenic function of islet-specific CD4+ T cells.

Original languageEnglish (US)
Pages (from-to)2654-2663
Number of pages10
JournalJournal of Immunology
Volume194
Issue number6
DOIs
StatePublished - Mar 15 2015
Externally publishedYes

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Genome
Type 1 Diabetes Mellitus
T-Lymphocytes
Genes
Congenic Mice
Inbred NOD Mouse
Gene Regulatory Networks
Microarray Analysis
Computational Biology
Inbred C57BL Mouse
Growth and Development
Transcriptome
Genotype
Insulin
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Berry, G. J., Frielle, C., Luu, T., Salzberg, A. C., Rainbow, D. B., Wicker, L. S., & Waldner, H. (2015). Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function. Journal of Immunology, 194(6), 2654-2663. https://doi.org/10.4049/jimmunol.1401288

Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function. / Berry, Gregory J.; Frielle, Christine; Luu, Thaiphi; Salzberg, Anna C.; Rainbow, Daniel B.; Wicker, Linda S.; Waldner, Hanspeter.

In: Journal of Immunology, Vol. 194, No. 6, 15.03.2015, p. 2654-2663.

Research output: Contribution to journalArticle

Berry, GJ, Frielle, C, Luu, T, Salzberg, AC, Rainbow, DB, Wicker, LS & Waldner, H 2015, 'Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function', Journal of Immunology, vol. 194, no. 6, pp. 2654-2663. https://doi.org/10.4049/jimmunol.1401288
Berry, Gregory J. ; Frielle, Christine ; Luu, Thaiphi ; Salzberg, Anna C. ; Rainbow, Daniel B. ; Wicker, Linda S. ; Waldner, Hanspeter. / Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function. In: Journal of Immunology. 2015 ; Vol. 194, No. 6. pp. 2654-2663.
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