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Differential Integrin Adhesome Expression Defines Human Natural bioRxiv preprint doi: https://doi.org/10.1101/2020.12.01.404806; this version posted December 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Differential integrin adhesome expression defines human natural killer cell residency and developmental stage Everardo Hegewisch Solloa1, Seungmae Seo1, Bethany L. Mundy-Bosse2, Anjali Mishra3,a, Erik Waldman4,b, Sarah Maurrasse4,b, Eli Grunstein4, Thomas J. Connors5, Aharon G. Freud2,6, and Emily M. Mace1 1Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York NY 10032 2Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210 33Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210 4Department of Otolaryngology - Head and Neck Surgery, Columbia University Medical Center, New York, New York 10032 5Department of Pediatrics, Division of Pediatric Critical Care and Hospital Medicine, Columbia University Irving Medical Center, New York, NY 10024 6Department of Pathology, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210 aCurrent affiliation: Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA bCurrent affiliation: Department of Surgery, Section of Otolaryngology–Head Neck Surgery, Yale School of Medicine, New Haven, CT, USA Natural killer (NK) cells are innate immune cells that reside and lineage potentials (6–12). The stage 4 NK cell subset within tissue and circulate in peripheral blood. As such, they can be further delineated to stages 4A and 4B by expression interact with a variety of complex microenvironments, yet how of NKp80 at stage 4B (13). The predominant NK cell sub- NK cells engage with these varied microenvironments is not well sets in peripheral blood are stages 4B, 5 and 6, often defined documented. The integrin adhesome represents a molecular as CD56bright, CD56dim and terminally mature CD56dim network of defined and predicted integrin-mediated signaling respectively, however circulating NK cell and innate lym- interactions. Here, we define the integrin adhesome expression phoid cell precursors are also found at low frequencies (7– profile of NK cells from tonsil, peripheral blood and those de- + rived from hematopoietic precursors through stromal cell co- 9, 13, 14). CD34 NK progenitor cells are thought to enter culture systems. We report that the site of cell isolation and NK circulation from bone marrow and subsequently seed periph- cell developmental stage dictate differences in expression of ad- eral sites to continue NK maturation; functionally mature NK hesome associated genes and proteins. Furthermore, we define cells then re-enter circulation in peripheral blood as stage 4B differences in cortical actin content associated with differential or stage 5 effectors (7). As such, stage 5 cells predominate in expression of actin regulating proteins, suggesting that differ- circulation, express perforin and granzymes at baseline, and ences in adhesome expression are associated with differences in are considered poised for cytolytic function following recruit- cortical actin homeostasis. Together, these data provide new un- ment to sites of infection or inflammation. Tissue resident derstanding into the diversity of human NK cell populations and NK cells are generally considered to be stage 4 (CD56bright) how they engage with their microenvironment. NK cells, yet have distinct phenotypes from peripheral blood natural killer cell | integrin | adhesome | stage 4 cells and are thought to perform more regulatory func- Correspondence: [email protected] DRAFTtions (4, 10). The differential expression of chemokine recep- tors and adhesion molecules on NK cells in peripheral blood Introduction and tissue have been implicated in the mechanisms that medi- ate tissue localization and homing of distinct NK cell subsets Human natural killer (NK) cells are commonly defined as (4, 5). CD56+CD3− cytotoxic innate lymphocytes and they play a critical role in identifying and killing virally infected or ma- Integrins act as bidirectional signaling hubs between cellular lignant cells. The importance of NK cells in the control of vi- machinery, namely the actin cytoskeleton, and the extracel- ral infections is underscored by the clinical course of patients lular microenvironment. As such integrins play particularly with NK cell deficiencies who experience severe and often critical roles in lymphocyte activation, immune synapse for- life-threatening viral infections (1–3). In addition to circulat- mation and B, T, and NK cell development (15–20). Inte- ing NK cells found in peripheral blood, tissue resident NK grin function is finely tuned and can be regulated by changes cell populations are present in organs including liver, lung, in expression, localization and affinity, and their specificity spleen, bone marrow, and secondary lymphoid tissue, where for ligand is dictated in part by the pairing of 18 alpha sub- they serve unique cytotoxic and regulatory functions (4, 5). units and 8 beta subunits to form at least 24 unique non- NK cell maturation is marked by the progressive gain of NK covalently linked obligate heterodimers. NK cells express cell-associated receptors and functions, and NK cell devel- leukocyte-specific b2 integrins that mediate cell-cell inter- opmental subsets can be defined as stages 1-6, which are actions, as well as those that are more broadly expressed stages of maturation that represent unique cell phenotypes and facilitate cell-matrix interactions, including b1 and b7 Hegewisch Solloa et al. | bioRχiv | December 1, 2020 | 1–20 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.01.404806; this version posted December 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. integrins (21–27). Previous studies have shown that VLA- by RNA-Seq revealed that both tissue residency and devel- 4 (a4b1, CD49d/CD29) and VLA-5 (a5b1, CD49e/CD29) opmental stage are determinants of unique gene expression heterodimers are expressed by NK cells found in periph- profiles (Fig. 1A). This analysis revealed that the overall gene eral blood and mediate NK cell adhesion to fibronectin (27). expression is more significantly affected by tissue specificity LFA-1, the aLb2 heterodimer (CD11a/CD18), and Mac-1, (PC1: 57% of variance) than the developmental stages (PC2: the aMb2 heterodimer (CD11b/CD18), mediate NK cell ad- 12% of variance). As such, when phenotypically equivalent hesion to ICAM-1 on target cells, leading to signaling and stage 4B and 5 cells from peripheral blood or tissue were actin remodeling which stabilize the immunological synapse compared, the two subsets from the same tissue clustered of NK cells (24–26). Furthermore, a subpopulation of NK more closely than the two subsets of the same developmental cells in human peripheral blood are detected with LFA-1 in stage (Fig. 1A, Supp. Fig. 2). To further understand the a partially activated conformation, suggesting that conforma- genes contributing to the separation observed between PB tional regulation, in addition to expression, is a feature of and tonsil NK cells, we plotted the 18,475 genes used for integrin phenotypes (25). Differences in tissue residency and PCA by their PC1 loading weights (Fig. 1A). Genes asso- function between NK cell developmental subsets suggest that ciated with the generally immature phenotype of tonsil NK distinct integrin repertoires mediate critical functions in lym- cells, such as GZMK, KLRC1, and IL7R, were primarily rep- phocyte development, activation and migration. However, resented by negative weights in PC1, consistent with the clus- the expression patterns of integrins and their associated sig- tering of tonsil subsets with negative PC1 values (Fig. 1B). In naling networks from NK cell subsets have not been compre- contrast, peripheral blood NK cells were marked by positive hensively described. PC1 weights of genes related to NK cytotoxicity, activation, The integrin adhesome is the in silico molecular catalogue and KIR receptors (B3GAT1, KLRB1, KIR3DL2, KIR2DL1, of signaling protein interactions that occur in response to in- and IFNGR1) (Fig. 1B). This distribution of gene sets across tegrin engagement with ligands, including extracellular ma- PC1 suggested that the differences between the transcriptome trix (ECM) components and cell adhesion molecules (28– of tonsil and peripheral blood NK cell subsets also reflected 32). While integrin adhesion complexes are more dynamic differences in the predominant stages of NK cell maturation in lymphocytes than in larger, slower-moving cells, compo- found at these sites. In addition, we found cytoskeleton-
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