Spatial and Temporal Mapping of Human Innate Lymphoid Cells Reveals Elements of Tissue Specificity

Abstract

Highlights d In contrast to mice, human ILCs are less strictly compartmentalized d ILC subset composition is differentially impacted by tissue localization d Tissue environment drives transcriptional heterogeneity in a subset-dependent way d ILC1 exhibit greater transcriptional heterogeneity in mucosal versus lymphoid sites SUMMARY Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner. Tissue-specific distinctions are particularly apparent for ILC1 populations, whose distribution was markedly altered in obesity or aging. Furthermore, the degree of ILC1 population heterogeneity differed substantially in lymphoid versus mucosal sites. Together, these analyses comprise a comprehensive characterization of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues.

Tissue Determinants of Human NK Cell Development, Function, and Residence

“…By contrast, immature subsets populating LLN and MLN contained the two precursor subsets (CD56 bright CD127 + CD161 + ) along with lower frequencies of five immature NK cell states (clusters 3-7) ( Figure 7D; Table S6). Although CD127 is also a marker for innate lymphoid cells (ILC) (Vivier et al, 2018), we did not detect substantial frequencies of CD127 + RORgt + ILC3s (Li et al, 2018;Yudanin et al, 2019) among CD56 + cells from LLN, gut, and spleen or the other sites examined ( Figure S7A). Moreover, the transcriptional profile of spleen and LLN NK cell subsets (Figure 4) was distinct from that of human ILC subsets in different sites recently reported (Yudanin et al, 2019; Figure S7B).…”

“…Although CD127 is also a marker for innate lymphoid cells (ILC) (Vivier et al, 2018), we did not detect substantial frequencies of CD127 + RORgt + ILC3s (Li et al, 2018;Yudanin et al, 2019) among CD56 + cells from LLN, gut, and spleen or the other sites examined ( Figure S7A). Moreover, the transcriptional profile of spleen and LLN NK cell subsets (Figure 4) was distinct from that of human ILC subsets in different sites recently reported (Yudanin et al, 2019; Figure S7B). Together, these data provide further evidence that the prevalent NK populations in LN likely represent precursor NK cells and NK subsets maintained in less differentiated states compared to other peripheral sites.…”

“…Clustering groups within PCA was predicted by pcaplot function of the pcaExplorer library (Marini and Binder, 2019). The hit counts table for the ILC study (GEO: GSE126107) (Yudanin et al, 2019) was downloaded and used to compare the transcriptional profile of ILC subsets to CD56 bright CD16 -NK cell subsets from this study.…”

The balance of power: innate lymphoid cells in tissue inflammation and repair

“…Moreover, since the gut may serve as the portal for inflammatory TL1A-producing macrophages and α 4 β 7 + , T-BET + ILCs in the synovial fluid (132), additional studies are needed to know whether anti-TL1A therapy or blockade of gut-derived α 4 β 7 + lymphocytes will limit extraintestinal ILC inflammation (154,155). In addition, sustained inflammation and pulmonary production of IL-25 in idiopathic pulmonary fibrosis liminary data show that the expansion of inflammatory ILC3s in multiple sclerosis is reduced following anti-CD25 therapy (161), but additional analysis of these populations from inflammatory tissue is needed to define novel molecular targets (162). Clinical studies coupled with emerging sequencing technologies that offer comprehensive genomic characterization of tissue-specific ILC subsets will be critical in identifying ILC targets that can be therapeutically manipulated to treat human disease.…”

New approaches to the study of immune responses in humans

“…As such, the cell-cell interaction patterns are likely to differ across tissues, and a challenge for the future will be to understand how this next layer of regulation-the organismal level, with its interactions between tissues, shape human immune function and determine immune competence at organism level. At the moment, sampling humans across multiple tissues is only possible using cadaver donors, and such studies are beginning to provide interesting insights into the tissue-specific immune cell compartments and niches in such human donors (Meng et al 2017;Yudanin et al 2019).…”