Abstract
The CD1d-restricted Vα14 invariant NKT (iNKT) cell lineage in mice (Vα24 in humans) represents an evolutionary conserved innate-like immune cell type that recognizes glycolipid antigens. Because of their unique ability to promptly secrete copious amounts of both pro-inflammatory and anti-inflammatory cytokines, typically produced by different T helper cell types, iNKT cells are implicated in the regulation of various pathologic conditions such as infection, allergy, autoimmune disease, maintenance of transplantation tolerance, and cancer. This striking multifaceted role in immune regulation is correlated with the presence of multiple functionally distinct iNKT cell subsets that can be distinguished based on the expression of characteristic surface markers and transcription factors. However, to date it, remains largely unresolved how this puzzling diversity of iNKT cell functional subsets emerges and what factors dictate the type of effector cell differentiation during the thymic differentiation considering the mono-specific nature of their T cell receptor (TCR) and their selecting molecule CD1d. Here, we summarize recent findings focusing on the role of TCR-mediated signaling and discuss possible mechanisms that may influence the sub-lineage choice of iNKT cells.
Highlights
Innate-like T lymphocytes are a special group of immune cells assumed to play important immunoregulatory functions by linking and orchestrating the functions of multiple cell types of the innate and adaptive arms of the immune system [1, 2].The invariant NKT cells, often referred to as Vα14 iNKT cells in mice (Vα24 in humans), represent an evolutionary conserved innate-like immune cell type characterized by the expression of a unique semi-invariant T cell receptor (TCR)
The development of the iNKT cell lineage proceeds in the thymus, where the precursor cells that successfully assembled their antigen receptor through recombination mediated by the recombination-activating gene (RAG) are positively selected on CD1d-expressing cortical CD4+CD8+ double-positive (DP) thymocytes [49]
There is currently no clear consensus on how promyelocytic leukemia zinc finger (PLZF) is induced, as it was shown that TCR stimulation is not sufficient to induce PLZF expression on pre-selection DP thymocytes [56], suggesting other unknown signals are likely to be required for the development of PLZFexpressing innate T cells such as iNKT
Summary
Innate-like T lymphocytes are a special group of immune cells assumed to play important immunoregulatory functions by linking and orchestrating the functions of multiple cell types of the innate and adaptive arms of the immune system [1, 2].The invariant NKT (iNKT) cells, often referred to as Vα14 iNKT cells in mice (Vα24 in humans), represent an evolutionary conserved innate-like immune cell type characterized by the expression of a unique semi-invariant T cell receptor (TCR). Recent publications have demonstrated the presence of multiple functionally distinct subsets with discrete cytokine polarization within the iNKT cell lineage that can be distinguished based on the expression of characteristic surface markers and transcription factors (Table 1) [25, 26].
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