cells Review Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System Louise A. Johnson and David G. Jackson *   Citation: Johnson, L.A.; Jackson, D.G. Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System. Cells 2021, 10, 2061. https://doi.org/ 10.3390/cells10082061 Academic Editor: Alessandro Poggi Received: 6 July 2021 Accepted: 8 August 2021 Published: 12 August 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; louise.johnson@imm.ox.ac.uk * Correspondence: david.jackson@imm.ox.ac.uk Abstract: Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothe- lium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy. Keywords: lymphatic endothelium; hyaluronan; dendritic cell; T cell; macrophage; trafficking; immune cell; LYVE-1; CD44; glycocalyx 1. Introduction The lymphatics play multiple roles in maintaining homeostasis in virtually all tissues through the uptake and drainage of interstitial fluids and the transport of electrolytes, dietary lipids, cholesterol, extracellular matrix and other dissolved macromolecules for appropriate degradation or delivery to the systemic blood circulation [1,2]. Although frequently overlooked by immunologists, the lymphatics are also integral to the immune system, insofar as they act as conduits for the migration of immune cells from tissues to draining lymph nodes (dLNs) for the generation, maintenance and modulation of antigen- specific immune responses [3–7], and later for the removal of phagocytes, apoptotic cell bodies and tissue debris during the repair of injured and inflamed tissues [8,9]. This continuous flow of information between tissues and downstream lymph nodes enables small numbers of patrolling antigen-presenting dendritic cells (DCs), recirculating memory T cells (T RCM ) and regulatory T cells (T REG ) to maintain constant surveillance for microbial or viral infection through a local neighbourhood watch system, licensed by their expression of CCR7, the receptor for the key chemokine CCL21 that directs lymphatic entry [10–15]. Moreover, in response to inflammation, the local release of cytokines such as IL-1, TNFα and INFγ induces large-scale mobilisation of resident DCs within tissues as well as an influx of T cells, monocytes and neutrophils from the circulation, all of which leads to a dramatic increase in immune cell trafficking through afferent lymphatics for the purpose of expanding and modifying immune responses in the dLNs [3,16–18]. Given the obvious Cells 2021, 10, 2061. https://doi.org/10.3390/cells10082061 https://www.mdpi.com/journal/cells