| The immune system is comprised of the innate arm and the adaptive arm that work together to protect the body from infections from foreign pathogen and is highly regulated to ensure effective immune response. Invariant Nature Killer T (iNKT) cells belong to the innate arm but have many characteristics of an adaptive immune cell. iNKT cells produce copious amounts of cytokines within minutes to hours after stimulation. They develop in the thymus and share a common precursor to conventional CD4 and CD8 T cells at the DP thymocyte stage, where they get positively selected into lineage. iNKT cells express an invariant Valpha14-Jalpha18 TCR alpha chain, that recognize glycolipids, presented on CD1d molecules. After selection into lineage, iNKT cell proliferate and differentiate into functional subsets analogous to the T helper cells, (NKT1, NKT2 and NKT17).;NKAP is a transcriptional repressor that associates with Hdac3. NKAP is required for HSC survival, early T cell development at DN3 to DP transition and for conventional T cell maturation. In this dissertation I will demonstrate NKAP's role in iNKT cell biology. Using the CD4-cre NKAP conditional knock out (cKO) model, I will show NKAP's obligatory role in the positive selection of iNKT cells at the DP thymocyte stage. This role is cell intrinsic and is not due to decreased DP thymocytes survival or the inability of thymocytes to rearrange the Valpha14-Jalpha18 TCR alpha chain. NKAP may work with Hdac3 to regulate the positive selection of DP thymocytes to iNKT cell lineage, as CD4-cre Hdac3 cKO mice exhibit a similar block in iNKT cell positive selection. Using the PLZF-cre NKAP cKO model, where NKAP is deleted after selection into the iNKT lineage, NKAP is required for iNKT cell proliferation and differentiation into ROR-gammat expressing NKT17 cells. The requirement of NKAP is cell intrinsic and is not due to altered iNKT cell homeostasis, TGF-beta signaling and mTOR signaling. Overexpression of PLZF compensated for the loss of NKAP in the differentiation of NKT17 cells, but did not restore the proliferation defect or decreased iNKT cell numbers, demonstrating that NKAP has distinct functions during proliferation and NKT17 differentiation. Therefore, NKAP is required at 3 distinct steps in iNKT development and differentiation: positive selection of iNKT cells, proliferative burst during thymic development and differentiation into IL-17 producing NKT17 cells. |
