Stages versus subsets: Invariant Natural Killer T cell lineage differentiation

Invariant Natural Killer T (iNKT) cells represent a population of innate T lymphocytes which act as ‘first-responders’ to infection. While they have long been considered a versatile cell, capable of secretion of multiple cytokines upon activation, recent evidence now indicates that distinct lineages of iNKT cells with unique transcriptional and cytokine profiles exist in different peripheral tissue and as such represent ‘fine-tuning’ of these cells, which act as mediators between the innate and adaptive immune systems. Here we discuss the molecules regulating the differentiation of iNKT cell lineages, the transcription factors associated with their development, and the role of E protein transcription factors and their negative regulators the Id proteins, as these cells develop from immature progenitor cells to terminally differentiated cells in peripheral tissue.