Reduced expression of cyclin-depedent kinase inhibitor Cdkn2c reduced IL-2 production by CD4+ T cells expressing the murine NZB-derived Sle2c1 susceptibility locus (47.22)

Abstract

Sle2c1 is a sublocus from the NZB-derived Sle2 locus found in the NZM2410 lupus-prone mouse. In addition to expanding the peritoneal cavity B1a cells, Sle2c1 significantly reduced IL-2 production by activated CD4+ T cells in vitro and is associated with a reduction of the Treg compartment, especially in Fas-deficient mice. The characterization of three Sle2c1 recombinants mapped the IL-2 deficiency to a short interval on chromosome 4 that contains the Cdkn2c gene. Cdkn2c encodes for p18INK4c (p18), a cyclin-dependent kinase inhibitor that regulates G1 cell cycle arrest. We have found a novel SNP in the Cdkn2c promoter that is associated with a significantly reduced expression of this gene in CD4+ T cells. Activated CD4+ T cells from B6.p18-/- mice produced significantly less IL-2 than B6 controls, demonstrating that a dysregulated cell cycle interferes with IL-2 production. Interestingly, we have also found that p18 reduced expression, either in B6.Sle2c1 or B6.p18-/- mice, is also associated with an expansion of the B1a cells compartment. Overall these results show that a dysregulated cell cycle affects CD4+ T cell and B cell homeostasis and is associated with lupus susceptibility, either through an expansion of the b1a cells, a reduced IL-2 production, or both.