The ins and outs of type I iNKT cell development

Abstract

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.

Keywords: CD1d; Innate lymphocytes; NKT cells; Natural killer T; T cell development; iNKT.

Figure 1:

NKT cell development and differentiation. NKT cells develop in the thymus and can be characterized by flow cytometry for surface and intracellular markers. In the most prominent developmental model, NKT cells branch off from conventional T cell development at the double positive stage where they are selected by strong SLAM:SLAM and CD1d:TCR signals that result in Egr2 upregulationandsubsequentlyPLZF upregulation. They progress through 4 stages of development (0–3) and differentiate into NKT1, 2, and 17 cells. Both stage 2 and 3 are exported from the thymus. Another developmental pathway starts in the DN4 stage of cell development and bypasses the double positive stage to produce mature, DN NKT1-like cells.

Figure 2:

Extrinsic factors that effects NKT cell development. NKT cell development requires input from other cell types. CD1d expression, recycling, and antigen exchange alters NKT cell positive and negative selection. Additionally, specific cell-cell interactions, such as CD1d:TCR, SLAM:SLAM, CD80/86:CD28, and ICOS-L:ICOS, greatly influence NKT cell population development. Moreover, factors such as lymphotoxin α, vitamin D, CCL19/21, and IL-15 have a significant impact on NKT cell development. IL-15, in particular, must be presented in trans to NKT cells by medullary thymic epithelial cells.

Figure 3:

NKT cells must balance many signals for development and expansion. NKT cell development involves extremely strong TCR and SLAM signals that reprogram the cell. This requires activation of survival (NF-κB) and proliferation (c-Myc) pathways as well as metabolic balancing (PI3K, mTOR, AMPK) and transcriptional activation. During this time, the NKT cell is also upregulating multiple lineage specific transcription factors to control differentiation and effector functions.