Liver type 1 innate lymphoid cells lacking IL-7 receptor are a native killer cell subset fostered by parenchymal niches

Abstract

Group 1 innate lymphoid cells (G1-ILCs), including circulating natural killer (NK) cells and tissue-resident type 1 ILCs (ILC1s), are innate immune sentinels critical for responses against infection and cancer. In contrast to relatively uniform NK cells through the body, diverse ILC1 subsets have been characterized across and within tissues in mice, but their developmental and functional heterogeneity remain unsolved. Here, using multimodalin vivoapproaches including fate-mapping and targeting of the interleukin 15 (IL-15)-producing microenvironment, we demonstrate that liver parenchymal niches support the development of a cytotoxic ILC1 subset lacking IL-7 receptor (7R−ILC1s). During ontogeny, fetal liver (FL) G1-ILCs arise perivascularly and then differentiate into 7R−ILC1s within sinusoids. Hepatocyte-derived IL-15 supports parenchymal development of FL G1-ILCs to maintain adult pool of 7R−ILC1s. IL-7R+(7R+) ILC1s in the liver, candidate precursors for 7R−ILC1s, are not essential for 7R−ILC1 development in physiological conditions. Functionally, 7R−ILC1s exhibit killing activity at steady state through granzyme B expression, which is underpinned by constitutive mTOR activity, unlike NK cells with exogenous stimulation-dependent cytotoxicity. Our study reveals the unique ontogeny and functions of liver-specific ILC1s, providing a detailed interpretation of ILC1 heterogeneity.

Layered origins of lymphoid tissue inducer cells

“…This concept holds true for the LTi cell and ILC3 38,46,58,59 lineages 32 (Figure 2). Studies have shown that also ILC1 4,88–90 and ILC2 91 have an embryonic wave, seeding embryonic tissues such as fetal liver, LN anlagen, gut and lung and being gradually replaced during life by cells derived from bone‐marrow residing progenitors. To better identify the descendants of these specific waves, precise fate‐mapping models are required.…”

Group 1 ILCs: Heterogeneity, plasticity, and transcriptional regulation

“…24,53,54 Despite differential IL7R expression, ILC1s are independent of IL7 and are not diminished in IL7 knockout mice. 24 Functionally, liver ILC1s play an important role, in a nonredundant manner, to control cancer metastases to liver and also provide protection against acute liver injury. 56,57 Three clusters of liver NK cells were observed in a recent scRNAseq analysis.…”

“…Several transcriptomic and proteomic studies have identified multiple transcription factors, including Nfil3, ID2, TOX, TCF1, and PLZF1 that orchestrate ILC development downstream of CLPs. 16,[18][19][20][21][22][23][24][25][26] The earliest common progenitors that differentiate from CLPs and can give rise to all three groups of ILCs are termed early innate lymphoid progenitors (EILPs).…”

“…Based on PLZF fate mapping and lack of Eomes expression, fetal liver group 1 ILCs are generally considered ILC1s. 24,55 Adult mouse liver NK cells and ILC1s segregate well based upon CD49a and Eomes expression as described earlier. In our meta cell analysis of scRNA-seq data we observed that adult liver ILC1s highly expressed Fgl2, Cd7, Cxcr6, S100a4, S100a6, and Gzmb transcripts relative to other tissue-specific and nonspecific Group1 ILCs.…”

“…24 IL7R + ILC1s highly express RORα and are the most affected subset in RORα KO mice. 24 As far as a developmental relationship between these two subsets is concerned, fetal liver group1 ILCs can partially contribute to adult IL7R − ILC1 but not IL7R + ILC1s. However, there is ambiguity in this regard as another study reported that these two subsets represent different effector maturation stages of ILC1s and IL7R + ILC1 can differentiate into IL7R − ILC1s.…”