SNPs upstream of the minimal promoter control IL-2 expression and are candidates for the autoimmune disease-susceptibility locus Aod2/Idd3/Eae3.
IL-2, a T-cell growth and differentiation factor, plays an important role in immune homeostasis. Previously, we identified IL2 as a candidate for Aod2, a quantitative trait locus (QTL) controlling susceptibility to autoimmune ovarian dysgenesis (AOD) induced by day 3 neonatal thymectomy. Here, we report the identification of single-nucleotide polymorphisms (SNPs) in a region upstream of the minimal IL2 promoter (-2.8 kb to -300 bp), which distinguish AOD-susceptible A/J and AOD-resistant C57BL/6J (B6/J) mice. Six of the SNPs (-1010 C --> T, -962 C --> T, -926/-925 Delta Delta --> AC, -921 T --> C, -914 T --> C and -674 G --> A) contribute to the enhanced transcriptional activity of the extended B6/J promoter relative to A/J. Importantly, the -1010 SNP resides within a canonical AP-1-binding motif with the C --> T transition at this site abrogating AP-1 binding. Moreover, these SNPs segregate with differential production of IL-2 by CD4(+) T cells as well as susceptibility alleles at Idd3 and Eae3, QTL controlling insulin-dependent diabetes mellitus and experimental allergic encephalomyelitis. These are the first SNPs identified within the extended murine IL2 promoter that control differential IL-2 transcription in CD4(+) T cells, and, as such, they are not only candidates for Aod2, but are also candidates for a shared autoimmune disease-susceptibility locus underlying Idd3 and Eae3.
del Rio
R
R
Department of Medicine, University of Vermont, Burlington, VT 5405, USA.
Noubade
R
R
Subramanian
M
M
Saligrama
N
N
Diehl
S
S
Rincon
M
M
Teuscher
C
C
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D010049:Ovarian Diseases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D040641:Quantitative Trait Loci / Q000276:immunology; D013045:Species Specificity
D005819:Genetic Markers; D007376:Interleukin-2