Mouse iNKT cell development and functions are differentially regulated by SHIP-1 (HEM3P.288)

Abstract

Abstract The SH2-containing inositol phosphatase-1 (SHIP-1) is a 5’ inositol phosphatase known to negatively regulate the signaling product of phosphoinositide-3 kinase (PI3K), phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3). SHIP-1 can be recruited to a large number of inhibitory receptors expressed on iNKT cells. We hypothesized SHIP-1 deletion would have major effects on iNKT cell development by altering the thresholds for positive and negative selection. In SHIP-1 deficient animals, iNKT cell frequency and number are impaired when compared to littermate controls. However, using both mixed bone marrow chimera and mice conditionally deficient for SHIP-1 in the T cell lineage, we show iNKT cell development is globally intact, demonstrating SHIP-1 is not required intrinsically for iNKT cell development. In addition, although SHIP-1 is necessary extrinsically for iNKT positive selection, it is dispensable on CD1d positive selecting cells. Interestingly, SHIP-1 deficient iNKT cells display functional defects including reduced cytokine production. These results further our understanding of how iNKT cell activation is regulated and provide insights into the biology of this unique cell lineage.