Critical role for adhesion and degranulation promoting adaptor protein in homeostasis and function of invariant natural killer T cells

Abstract

Abstract Invariant natural killer T cells (iNKTs) are innate T lymphocytes that are critical in modulating immune response in cancer, infection and inflammation. However, the mechanisms that regulate iNKT cell development and function are not fully known. In the current study, we demonstrate that adhesion and degranulation promoting adaptor protein (ADAP) is dispensable for iNKT cell thymic development but is required for their peripheral maintenance. Strikingly, ADAP-deficient (Adap−/−) mice have significantly reduced iNKTs in the periphery that is associated with decreased surface expression of the critical homing receptor (CXCR6), homeostatic proliferation and increased apoptosis. Consistently, Adap−/− iNKTs have markedly reduced expression of pro-survival factors (PLZF, ICOS, GATA-3 and Id2) but increased levels of pro-apoptotic molecules (Bax, Bad and Bim). Functionally, Adap−/− iNKTs have significantly reduced cytokine production and bystander immune cell activation as well as poor anti-tumor response, both in vitro and in vivo. In agreement with these findings, ADAP-silenced human iNKTs have remarkably impaired cytokine production and cytotoxicity against leukemia targets in vitro. Mechanistically, preformed transcripts for interleukin (IL)-4 and IFN-g as well as several microRNAs are reduced in Adap−/− iNKTs. Additionally, these cells exhibit reduced capacity to form conjugates and have diminished actin polymerization at the immunological synapse. Collectively, our findings establish a novel and pivotal role for ADAP in iNKT cell homeostasis and function.