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Α2β1 Integrin Is Required for Optimal NK Cell Proliferation During Viral

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Α2β1 Integrin Is Required for Optimal NK Cell Proliferation During Viral α2β1 Integrin Is Required for Optimal NK Cell Proliferation during Viral Infection but Not for Acquisition of Effector Functions or NK Cell−Mediated Virus Control This information is current as of September 28, 2021. Colby Stotesbury, Pedro Alves-Peixoto, Brian Montoya, Maria Ferez, Savita Nair, Christopher M. Snyder, Shunchuan Zhang, Cory J. Knudson and Luis J. Sigal J Immunol published online 3 February 2020 http://www.jimmunol.org/content/early/2020/01/31/jimmun Downloaded from ol.1900927 Supplementary http://www.jimmunol.org/content/suppl/2020/01/31/jimmunol.190092 http://www.jimmunol.org/ Material 7.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 3, 2020, doi:10.4049/jimmunol.1900927 The Journal of Immunology a2b1 Integrin Is Required for Optimal NK Cell Proliferation during Viral Infection but Not for Acquisition of Effector Functions or NK Cell–Mediated Virus Control Colby Stotesbury, Pedro Alves-Peixoto, Brian Montoya, Maria Ferez, Savita Nair, Christopher M. Snyder, Shunchuan Zhang, Cory J. Knudson, and Luis J. Sigal NK cells play an important role in antiviral resistance. The integrin a2, which dimerizes with integrin b1, distinguishes NK cells from innate lymphoid cells 1 and other leukocytes. Despite its use as an NK cell marker, little is known about the role of a2b1in NK cell biology. In this study, we show that in mice a2b1 deficiency does not alter the balance of NK cell/ innate lymphoid cell 1 generation and slightly decreases the number of NK cells in the bone marrow and spleen without affecting NK cell maturation. NK cells deficient in a2b1 had no impairment at entering or distributing within the draining lymph node of ectromelia virus Downloaded from (ECTV)–infected mice or at becoming effectors but proliferated poorly in response to ECTV and did not increase in numbers following infection with mouse CMV (MCMV). Still, a2b1-deficient NK cells efficiently protected from lethal mousepox and controlled MCMV titers in the spleen. Thus, a2b1 is required for optimal NK cell proliferation but is dispensable for protection against ECTV and MCMV, two well-established models of viral infection in which NK cells are known to be important. The Journal of Immunology, 2020, 204: 000–000. http://www.jimmunol.org/ atural killer cells are leukocytes of the innate immune The phenotypes and functions of NK cells overlap extensively system that belong to the group 1 of innate lymphoid cells with those of ILC1s, the only other member of the group 1 ILCs. N (ILCs). After developing in the bone marrow, NK cells For example, both ILC1s and NK cells express the typical NK cell– circulate between blood and tissues patrolling the body for in- activating receptors NKp46 and, in B6 mice, NK1.1. Both ILC1s fections and tumors. Following viral infections, NK cells are and NK cells need the transcription factor T-bet for their devel- rapidly recruited from the blood to secondary draining lymph opment (11). Moreover, NK cells and ILC1s produce IFN-g upon nodes (dLNs) and other infected tissues, where they produce stimulation. Because of this, ILC1s can participate in virus control IFN-g, kill infected cells, and proliferate, playing a critical role in tissues (12). Yet, ILC1s and NK cells also exhibit differences as a first line of antiviral defense (1, 2). For example, C57BL/6 that make them unique. ILC1s are tissue resident and do not cir- by guest on September 28, 2021 (B6) mice, which are normally resistant to mouse CMV culate in the blood, whereas NK cells circulate in the blood and (MCMV) and ectromelia virus (ECTV), become susceptible are transient within tissues. NK cells but not ILC1s are cytolytic when NK cells are eliminated or dysfunctional (3–7). Also, in and express the transcription factor eomesodermin (Eomes) (13–16). humans, NK cell–deficient individuals become sick or succumb At the cell surface, the major differences between ILC1s and NK to normally non–life-threatening infections with human CMV cells is in the expression of integrins. ILC1s but not NK cells express or with varicella zoster (8–10). the integrin b3 and some but not all ILC1s express integrin a1(12). In contrast, NK cells but not ILC1s express the integrin aM (CD11b, Department of Microbiology and Immunology, Thomas Jefferson University, also expressed by other unrelated leukocytes) and the integrin a2(in Philadelphia, PA 19107 this study a2; also known as CD49b). ORCIDs: 0000-0002-6082-6838 (P.A.-P.); 0000-0002-1969-2911 (B.M.); 0000-0001- Integrins are cell surface heterodimeric receptors formed by an a- 6725-0459 (S.N.); 0000-0003-1370-7198 (C.M.S.); 0000-0001-6642-5472 (L.J.S.). and a b-chain (17). Integrins function in the adhesion of leukocytes Received for publication August 2, 2019. Accepted for publication January 5, 2020. to the endothelium and their extravasation into lymph nodes (LNs) This work was supported by grants from the National Institute of Allergy and Infec- and inflamed tissues. Integrins are also important for the displace- tious Diseases (NIAID) (R01AI110457 and R01AI065544) and the National Institute ment of leukocytes within tissues and can participate in their de- on Aging (AG048602 to L.J.S.). B.M. and C.J.K. were supported by Grant T32 AI134646 from the NIAID. P.A.-P. was partially supported by a Ph.D. fellowship (PD/ velopment and activation (18). a2 dimerizes with the integrin b1(in BD/128078/2016) from the M.D./Ph.D. Program of the University of Minho-School of this study b1; also known as CD29) to form a2b1 (also known as Medicine funded by the Fundac¸a˜oparaaCieˆncia e Tecnologia. Research reported in this VLA-2), a receptor for collagens type I and III. Of note, b1is publication used the Flow Cytometry and Animal Laboratory facilities at the Sidney Kimmel Cancer Center at Jefferson Health and was supported by the National Cancer thought to be the only partner of a2, whereas b1 can heterodimerize Institute of the National Institutes of Health under Award P30CA056036. with 12 different a-chains (19, 20), including a1(a1b1) in ILC1s. Address correspondence and reprint requests to Dr. Luis J. Sigal, Thomas Jefferson Notably, a2b1 is also expressed by human NK cells (21). University, 233 South 10th Street, Philadelphia, PA 19107. E-mail address: Despite a2 being a reliable NK cell marker, the role of a2b1in [email protected] the biology of NK cells is not well understood. When the Lanier The online version of this article contains supplemental material. group discovered a2 on murine NK cells, they also showed that Abbreviations used in this article: a2, integrin a2; b1, integrin b1; dLN, draining lymph node; dpi, day postinfection; ECTV, ectromelia virus; Eomes, eomesodermin; two different anti-a2 mAbs, DX5 and HMa2, do not block the GzmB, granzyme B; hpi, hour postinfection; ILC, innate lymphoid cell; LN, lymph binding of NK cells to collagen-coated plates, despite that HMa2 node; K181, MCMV K181; MCMV, mouse CMV; ndLN, nondraining LN; qRT-PCR, blocks the a2b1-dependent binding of platelets to collagen. In quantitative RT-PCR, . addition, the Lanier group demonstrated that immobilized anti-a2 Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 mAbs did not stimulate IFN-g production in NK cells, nor did www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900927 2 ROLE OF a2b1 INTEGRIN IN NK CELLS they block NK cell killing of YAC-1 cells (22, 23). Together, these (American Type Culture Collection; ATCC CRL-1972TM) with a multi- data suggested that a2b1 may not be essential for NK cell func- plicity of infection of 0.01 for 4–5 days postinfection (dpi) or until cyto- tion. Later, others showed that positive purification of NK cells pathic effect in culture was observed. Cells and supernatant were collected, centrifuged at 2600 3 g for 10 min, and resuspended in 10 ml of complete using DX5 mAb negatively affected their ability to produce IFN-g RPMI 1640 (Corning) supplemented with 10% FBS, 10 mM HEPES in vitro, kill target cells in vitro and in vivo, and impaired their (Corning), 1 mM sodium pyruvate (Corning), 100 U penicillin (Corning), motility in LNs (24). However, these data did not directly demon- and 100 mg/ml streptomycin (Corning). Debris were then lysed with a strate a physiological role for a2b1. More recently, it was shown Dounce homogenizer while on ice and spun. Supernatant was collected, transferred to ultracentrifuge tubes (Beckman Coulter), and spun at that NK cells interacted with collagen fibers in the dLNs of mice 50,000 3 g for 1 h at 4˚C. The supernatant was discarded, and the infected in the ear flaps with Toxoplasma gondii, and that admin- pellet was resuspended in 500 ml of complete RPMI 1640. V70 stocks istration of HMa2 in the ear flap decreased the presence of NK cells were produced by infecting BALB/c mice (.3 wk old) with 10 PFU of in T.
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