The ins and outs of type I iNKT cell development

•Unlike classic T cells, NKT cells differentiate into effector subsets in the thymus.•Survival is tightly controlled by NF-κB, Erk, AMPK, Egr2, TCF-1, RORγt, and miRs.•Proliferation is regulated by c-myc, mTOR, E proteins, and HDAC3.•Effector functions are dictated by PLZF, Egr2, GATA3, T-bet, AP-1, Notch, and HDAC3.•Extrinsic signals originate from both hematopoietic and epithelial cells. Natural killer T (NKT) cells are innate-like lymphocytes that bridge the gap between the innate and adaptive immune responses. Like innate immune cells, they have a mature, effector phenotype that allows them to rapidly respond to threats, compared to adaptive cells. NKT cells express T cell receptors (TCRs) like conventional T cells, but instead of responding to peptide antigen presented by MHC class I or II, NKT cell TCRs recognize glycolipid antigen in the context of CD1d. NKT cells are subdivided into classes based on their TCR and antigen reactivity. This review will focus on type I iNKT cells that express a semi invariant Vα14Jα18 TCR and respond to the canonical glycolipid antigen, α-galactosylceramide. The innate-like effector functions of these cells combined with their T cell identity make their developmental path quite unique. In addition to the extrinsic factors that affect iNKT cell development such as lipid:CD1d complexes, co-stimulation, and cytokines, this review will provide a comprehensive delineation of the cell intrinsic factors that impact iNKT cell development, differentiation, and effector functions – including TCR rearrangement, survival and metabolism signaling, transcription factor expression, and gene regulation.