Abstract
TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+ T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.
Highlights
Relatively recently has it been discovered that the innate immune system has a wide range of effector functions carried out by a multitude of innate lymphoid cell (ILC) subtypes
common lymphoid progenitors (CLPs) isolated from fetal liver and adult bone marrow (BM) were dependent on Notch for differentiation into an α4β7+Rorγt− lymphoid tissue inducer cells (LTi)-like cell precursor population, but Notch signals needed to be terminated for differentiation into mature RORγt expressing ILC3s and blocking a T-cell fate [2]
TOX, a transcriptional regulator that had been previously associated with CD4 T-cell development in the thymus, is a key regulator of innate lymphoid cell development
Summary
Relatively recently has it been discovered that the innate immune system has a wide range of effector functions carried out by a multitude of innate lymphoid cell (ILC) subtypes. Group 2 ILCs (ILC2s) depend on the transcriptional regulators RORα, TCF-1, and Bcl11b [3, 10,11,12] and like Th2 cells require GATA3 for their development and maturation [13]. PLZF, a transcriptional regulator required for natural killer T (NKT) cell function [26], identifies a subset of CHILP that can differentiate into all ILC lineages with the exception of LTi and cNK cells [27]. This suggests that upregulation of PLZF and loss of LTi cell fate potential may mark further specification of the ILC lineage.
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