Group 1 ILCs: Heterogeneity, plasticity, and transcriptional regulation

Abstract

Group 1 innate lymphoid cells (ILCs), comprising ILC1s and natural killer cells (NK cells), belong to a large family of developmentally related innate lymphoid cells that lack rearranged antigen-specific receptors. NK cells and ILC1s both require the transcription factor T-bet for lineage commitment but additionally rely on Eomes and Hobit, respectively, for their development and effector maturation programs. Both ILC1s and NK cells are essential for rapid responses against infections and mediate cancer immunity through production of effector cytokines and cytotoxicity mediators. ILC1s are enriched in tissues and hence generally considered tissue resident cells whereas NK cells are often considered circulatory. Despite being deemed different cell types, ILC1s and NK cells share many common features both phenotypically and functionally. Recent studies employing single cell RNA sequencing (scRNA-seq) technology have exposed previously unappreciated heterogeneity in group 1 ILCs and further broaden our understanding of these cells. Findings from these studies imply that ILC1s in different tissues and organs share a common signature but exhibit some unique characteristics, possibly stemming from tissue imprinting. Also, data from recent fate mapping studies employing Hobit, RORγt, and polychromic reporter mice have greatly advanced our understanding of the developmental and effector maturation programs of these cells. In this review, we aim to outline the fundamental traits of mouse group 1 ILCs and explore recent discoveries related to their developmental programs, phenotypic heterogeneity, plasticity, and transcriptional regulation.

Keywords: ILC development; ILC1s; NK cells; heterogeneity; innate lymphoid cells; plasticity; transcription factors.

Figure 1.. Heterogeneity of mouse ILC1s.

ILC1s are significantly heterogeneous and can be broadly divided into three major subsets. These subsets can be distinguished by IL7R expression as well as their effector and transcriptional requirements. The three major subsets are IL7R⁺ or IFNγ ILC1s, IL7R⁻ or Granzyme ILC1s (Gzm ILC1s) and RORγt ILC1s or Ex ILC3s. The distribution and abundance of these subsets varies across as well as within tissues. Key molecules that are either shared by or distinguish the three subsets are shown.

Figure 2.. Plasticity of mouse Group 1 ILCs.

ILCs are considered plastic because they have a significant tendency to transdifferentiate. Among group 1 ILCs, NK cells have a strong potential to transition into ILC1s under the influence of TGFβ, certain infections, cancer, and obesity. Similarly, ILC2s and ILC3s can also transdifferentiate into ILC1s under the influence of cytokines and infection. IL12, IL18 and IL1β mediate the transition from ILC2s to ILC1s. IL12 and infection also mediate transition from ILC3 to an ILC1 phenotype.