True Detective: Unraveling Group 1 Innate Lymphocyte Heterogeneity

Abstract

Innate lymphoid cells (ILCs) consist of a heterogeneous family of lymphocytes that regulate tissue homeostasis and can contribute to pathology in mice and humans. Mammalian group 1 ILCs are defined by the production of interferon (IFN)-γ and the functional dependence on the transcription factor T-bet. While recent studies demonstrate that group 1 ILCs consist of circulating mature natural killer (NK) cells and tissue-resident ILC1s, the functional, phenotypic, and developmental properties that distinguish these two cell lineages are often confusing and difficult to dissect. In this review, we critically evaluate the current knowledge of mammalian group 1 ILC heterogeneity and propose new inclusive nomenclature to clarify the roles of ILC1s and NK cells during homeostasis and disease.

Keywords: ILC; NK cell; group 1 ILCs; heterogeneity.

Figure 1.. Shared and Distinct Mouse Group 1 ILC Phenotypic Markers.

Mouse ILC1 and NK cells share the expression of certain cell surface markers and transcription factors across peripheral organs that cannot be used to define these cell lineages (during homeostasis and inflammation). Certain cell surface markers are also not homogenously expressed on all peripheral NK and ILC1. However, previous studies have identified stable surface markers of group 1 ILCs that do not change during inflammation (shown in black). Surface markers that may lose or gain expression during states of activation or inflammation, or are heterogeneously expressed in peripheral ILC1 are shown in red. Stable but heterogeneous (not expressed on all peripheral NK or ILC1) surface markers are shown in light grey.

Figure 2.. Group 1 ILC Plasticity in Mice and Humans.

Mature mammalian ILCs can be defined as distinct lineages through expression of the transcription factors T-bet, Eomes, Rorγt, and GATA3 at steady state. However, several studies have suggested that mature ILCs or ILC precursors found in tissues and the circulation can differentiate into mature ILC1 during inflammatory settings in vivo and in vitro. Here, we show a graphical illustration of the current factors and cytokines from the literature that may induce differentiation of indicated cell lineages into ILC1-like cells or NK cells. Arrows denote differentiation. Question marks denote differentiation pathways that are still not definitive.