T cell specific deletion of the phosphatase SHP1 decreases incidence and severity of experimental autoimmune encephalomyelitis (101.41)

Abstract

Abstract T cell activation is regulated by a dynamic balance between kinase and phosphatase activity. The tyrosine phosphatase SHP1 is a critical negative regulator of the immune system, and a proximal regulator of T cell receptor signaling. Here, we have utilized two novel models to study the deletion of SHP1 specifically in mature T cells. We have bred mice bearing a floxed SHP1 allele that deletes the majority of the gene with mice bearing an inducible Cre (Mx1 promoter). We also utilized a dominant negative allele of SHP1 whose expression requires Cre-driven recombination. By transferring mature T cells from these mice into T cell deficient hosts and subsequently inducing Cre expression we have isolated the effect of loss of SHP1 activity to T cells. We have determined that selective loss of this phosphatase in mature T cells dramatically attenuates experimental autoimmune encephalomyelitis (EAE). Both severity and incidence were decreased significantly in the conditional knockout and dominant negative mice relative to controls (mean max score 1.0, 1.7, and 2.7, respectively and mean incidence 29, 37 and 79%). These data differ from results in mice heterozygous for the motheaten allele, a naturally occurring SHP1 mutant, which exhibit EAE severity that is similar to or slightly worse than controls. Collectively, this suggests that lack of SHP1 activity in T cells may protect from disease, while deletion in other cell types may exacerbate susceptibility or symptoms.