Src-Like Adaptor Protein 2 regulates NKT lineage diversification

Abstract

Abstract Natural Killer T (NKT) cells are a class of αβ T cells that express a semi-invariant T Cell Receptor (TCR) and recognize glycolipids presented by the non-polymorphic MHC molecule, CD1d. NKT cells are considered to be innate-like lymphocytes because they produce a robust cytokine response within hours of stimulation. This ‘poised effector’ state is acquired during development in the thymus, where NKT precursors differentiate into one of three distinct subsets and acquire TH1, TH2, or TH17 effector functions. It is not known which signals control the divergence of NKT1, NKT2 and NKT17 subsets. We have identified a novel role for Src-like adaptor protein 2 (SLAP2) in regulation of NKT cell development. We have found that SLAP2-deficiency causes accumulation of thymic NKT cells and alters lineage diversification. In the absence of SLAP2, the frequency and number of thymic NKT2 and NKT17 cells are increased with a concomitant decrease in NKT1 cells. SLAP2−/− NKT cells express elevated levels of PLZF and higher levels of CD5, both of which are downstream of TCR signals. Although SLAP2 has been shown to negatively regulate TCR signaling in vitro, analysis of SLAP2−/− thymocytes revealed that TCR levels and signaling in CD4+CD8+ double positive thymocytes are normal. These data suggest that SLAP2 does not directly regulate TCR during development, in vivo. The numbers and proportions of conventional αβ T cells are largely unaffected by SLAP2-deficiency. In light of these data, we predict that SLAP2 regulates signals that are important for NKT lineage diversification but are dispensable for conventional T cell development.