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.