High Endothelial Venules

Abstract

Leukocytes, the cellular component of the immune system, are generated in primary lymphoid organs (bone marrow [BM] and thymus), but it is in the secondary lymphoid organs (SLOs) – which include peripheral lymph nodes (PLNs), mesenteric lymph nodes (MLNs), Peyer patches (PPs), spleen, appendix, and tonsils – that the immune response is orchestrated. These highly specialized organs collect antigen (Ag) and Ag-presenting cells (APCs) from distinct anatomical regions and serve as filters for Ag arriving from the periphery. Their extravascular environment is designed to optimize lymphocyte recognition of, and subsequent responses to, cognate Ag. A remarkable property of SLOs is their ability to recruit vast numbers of blood-borne B and T cells, which function as the backbone of the adaptive immune response. With the exception of the spleen, all SLOs contain specialized postcapillary and small collecting venules, called high endothelial venules (HEVs). These serve as the principal site of lymphocyte entry from the blood (1,2). HEVs express organspecific patterns of traffic molecules, which define a unique vascular address that is not found in other microvascular beds. These molecules coordinate the recruitment of circulating lymphocytes by promoting multistep adhesion cascades involving selectins, chemokines, integrins, and their respective ligands or counter-receptors (3,4). Selectins recognize ligands with extensive post-translational carbohydrate modifications. Indeed, HEVs express abundantly glycosylated adhesion molecule ligands, which serve to recruit circulating lymphocytes (5). Although selectins and their ligands are constitutively active, integrins require activation to bind to their ligands (6), and activation typically comes via signals delivered when chemokines or other chemoattractants presented on endothelial cells (ECs) in HEVs (which will be referred to throughout the chapter as high ECs, or HECs) bind their G-protein–coupled receptors (7). In this chapter, we discuss our current knowledge about the functional, structural, and molecular characteristics of HEVs that allow them to serve as the portal to SLOs. We examine the development of HEVs in normal and pathological settings, and explore how these unique microvessels respond to environmental cues. In addition, we discuss techniques to study these structures as well as emerging technologies that may pave the way for future discoveries.