Pre-B Cell Leukemia Homeobox 1is a novel susceptibility gene that regulate T cell functions. (123.2)

Abstract

Abstract Pre-leukemia homeobox (Pbx) 1 is a novel lupus susceptibility gene that regulates T cell activation and tolerance in both the NZM2410 lupus-prone mouse model and lupus patients. Lupus susceptibility is associated with the expression of a novel splice isoform Pbx1-d, which, when over expressed leads to an increased CD4+ T cell activation and a reduced induction of Tregs by retinoic acid. The exons encoding for the DNA binding domain and the Hox binding domain are deleted in Pbx-1d, predicting that this isoform functions as a dominant negative. To test this hypothesis, we used an osteogenesis model in which Pbx1 expression prevents differentiation. Pbx1-d expression in MC3T3 osteoblast progenitors mimicked the effect of shRNA Pbx1 in accelerating osteoblast differentiation. Furthermore, Pbx-1d binding to the SOX3 promoter was weaker than that of the full-length Pbx1-b isoform, and SOX3 expression was attenuated in Pbx1-d transfected cells. These results demonstrated that Pbx1-d functions as a dominant negative. C57BL/6 transgenic mice expressing Pbx1-d in their CD4+ T cells show an age-dependent increased in CD4+ T cell activation, with an expansion of CD44+ CD4+ memory cells, and the production of anti-nuclear autoantibodies. These results demonstrate that Pbx1 represents a novel regulator of T cell activation, whose impaired function leads to systemic autoimmunity.