Development, differentiation, and diversity of innate lymphoid cells

Abstract

Recent years have witnessed the discovery of an unprecedented complexity in innate lymphocyte lineages, now collectively referred to as innate lymphoid cells (ILCs). ILCs are preferentially located at barrier surfaces and are important for protection against pathogens and for the maintenance of organ homeostasis. Inappropriate activation of ILCs has been linked to the pathogenesis of inflammatory and autoimmune disorders. Recent evidence suggests that ILCs can be grouped into two separate lineages, cytotoxic ILCs represented by conventional natural killer (cNK) cells and cytokine-producing helper-like ILCs (i.e., ILC1s, ILC2s, ILC3s). We will focus here on current work in humans and mice that has identified core transcriptional circuitry required for the commitment of lymphoid progenitors to the ILC lineage. The striking similarities in transcriptional control of ILC and T cell lineages reveal important insights into the evolution of transcriptional programs required to protect multicellular organisms against infections and to fortify barrier surfaces.

Figure 1. Refined lineage map for the development of ILC lineages

All lymphoid lineages are the progeny of the common lymphoid progenitor (CLP). After the branchpoint with the B and T lineages an ILC-restricted progenitor may exist (CILP). Downstream of the CILP, two main ILC lineages can be discriminated, killer ILC and helper-like ILC. Killer ILC are represented by cNK cells and helper-like ILC are composed of the various cytokine-producing ILC subsets (i.e., ILC1, ILC2, ILC3). While helper-like ILC express IL-7Rα and require GATA-3 for differentiation, killer ILC do not express IL-7Rα and are normally represented in GATA-3-deficient mice. All helper-like ILC (but not killer ILC) differentiate from the Id2⁺ CHILP. A PLZF⁺ CHILP population has been identified that has more restricted differentiation potential. A precursor/progeny relation between PLZF⁻ and PLZF⁺ CHILP needs to be determined. CLP: common lymphoid progenitor; CILP: common ILC progenitor; CHILP: comon helper-like ILC progenitor; NKP: cNK-restricted progenitor