Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection

Abstract

The study of the immune system has shifted from a purely dichotomous separation between the innate and adaptive arms to one that is now highly complex and reshaping our ideas of how steady-state health is assured. It is now clear that immune cells do not neatly fit into these two streams and immune homeostasis depends on continual dialogue between multiple lineages of the innate (including dendritic cells, innate lymphoid cells, and unconventional lymphocytes) and adaptive (T and B lymphocytes) arms together with a finely tuned synergy between the host and microbes which is essential to ensure immune homeostasis. Innate lymphoid cells are critical players in this new landscape. Here, we discuss recent studies that have elucidated in detail the development of ILCs from their earliest progenitors and examine factors that influence their identification and ability to drive immune homeostasis and long-term immune protection.

Keywords: homeostasis; innate immunity; innate lymphoid cells; mucosal immunity; protection.

Figure 1

(A) Transcriptional regulation of ILC development from the common lymphoid progenitor (CLP) to mature ILC subsets 1, 2, and 3. It is now clear that the CLP transits through a series of intermediates including the early innate lymphoid progenitor (EILP) which in contrast with stages both preceding and following the EILP, downregulate the expression of IL‐7R. (B) Differential regulation of transcription factors and surface receptors is both dynamic and essential for diversification of ILC subsets

Figure 2

Gene regulatory network illustrating the involvement of key transcription factors in NK cells, ILC1, ILC2, and ILC3 development using BioTapestry software (Version 7.1.1m, biotapestry.org). Critical extracellular signals influencing ILC functions and mediating ILC plasticity are depicted. Networks were designed based on ChIP data or reporter assays61, 79, 91, 92, 102, 176, 177, 178, 179, 180 (thick lines) together with gene deletion or overexpression systems (regular lines).18, 19, 40, 43, 44, 57, 58, 59, 60, 61, 64, 72, 74, 75, 78, 79, 85, 86, 87, 89, 90, 91, 92, 93, 95, 98, 110, 118, 128, 169, 174, 176, 177, 178, 179, 180, 182, 183, 184, 185, 186, 187 Nonexpressed genes are depicted in gray. Linkages are color‐coded for clarity only. The individual genes are shown in schematic form only. The lines indicate the direct binding of the protein encoded by the indicated gene to the regulatory regions of the linked target genes, which leads to transcriptional activation or repression. Runx3, runt related transcription factor 3; Ets1, ETS proto‐oncogene 1; Ikzf2 (HELIOS), IKAROS family zinc finger 2; Ikzf3 (AILOS), IKAROS family zinc finger 3; Nfil3, nuclear factor, interleukin 3 regulated; Idb2, inhibitor of DNA binding 2; Socs3, suppressor of cytokine signaling 3; Id3, inhibitor of DNA binding 3; Tcf3 (E2A), transcription factor 3; Prf1, Perforin 1; Gzmb, granzyme B; Tcf7, transcription factor 7; Zeb2, zinc finger E‐box‐binding homeobox 2; Prdm1 (BLIMP1), PR domain zinc finger protein 1; Foxo1, forkhead box protein O1; Tox, thymocyte selection associated high mobility group box; Gata3, GATA binding protein 3; Itga1, integrin subunit alpha 1; Ifng, interferon‐gamma; Areg, amphiregulin; Il2ra, interleukin‐2 receptor subunit alpha; Icos, inducible T cell costimulator; Lta, lymphotoxin alpha; Tnf, tumor necrosis factor; Sox4, SRY‐Box 4; Rorc, RAR related orphan receptor C; Rora, RAR related orphan receptor A; Gfi1, growth factor independent 1; Bcl11b, B cell CLL/lymphoma 11B; Ahr, aryl hydrocarbon receptor. CD, cluster of differentiation

Figure 3

NK cells and ILC1 exhibit transitional phenotypes and functional alterations in response to tumors. (A) Multiple models have now been identified that highlight that deleted or unstable NKp46 results in ablation of TRAIL expression and impaired anti‐tumor activity. (B) Distinct NK cell and ILC1 subsets exist at steady‐state but under the influence of TGF‐β, tumor ILC1 acquire the expression of EOMES and surface markers such as CD49b normally expressed by NK cells

Figure 4

Regulation of ILCs at (A) steady‐state and during (B) infection and inflammation. (A) It is emerging that ILCs express a range of surface receptors that allow fine tuning of the positioning of different populations in tissues or between tissues dispelling the notion that ILCs are entirely sedentary within tissues. NK cells remain the most mobile with the capacity to move freely in the blood engaged in immunosurveillance, or to be recruited into tissues by modulating receptor expression. Only ILC1 appear to exhibit a truly tissue‐resident existence. (B) A proposed model for the replenishment of ILC in tissues. At steady‐state, slow proliferation of ILC within the tissues themselves allows the balance of subsets to be maintained. In an acute transient infection this may also be the case and that any temporary depletion would be rapidly replaced through enhanced local proliferation. If inflammation continues this might result in depletion that is not readily overcome by local proliferation and could lead to a state of “exhaustion” akin to that exhibited by T cells. Alternately, inflammation may drive differentiation of bone marrow progenitors and export in the blood to the affected tissues