Novel Regulators of Lymphocyte Trafficking across High Endothelial Venules

Abstract

The physiological recruitment of circulating lymphocytes from the blood into secondary lymphoid tissues is an essential homeostatic mechanism for the immune system because it allows lymphocytes to encounter efficiently both their specific cognate antigen and the regulatory cells with which they need to interact, to initiate, maintain, and terminate immune responses appropriately. This constitutive lymphocyte trafficking is mediated by high endothelial venules (HEVs), which are present in secondary lymphoid tissues other than the spleen. There is growing evidence that lymphocyte trafficking across HEVs involves at least three steps, namely, (i) tethering/rolling, (ii) arrest/firm adhesion/intraluminal crawling, and (iii) transendothelial migration (TEM). Although the mechanisms underlying the first two steps have been determined relatively well, the mechanism regulating TEM is only partially understood. In particular, the molecular mechanism driving lymphocyte movement from the apical to the basolateral surface of the endothelial cells (ECs) of HEVs remains ill defined. This step is crucial for successful lymphocyte extravasation, and is thus an important target for therapeutic intervention in various immunological diseases. Here, we review the molecular mechanisms governing lymphocyte-HEV interactions, and highlight possible roles for two HEV proteins, i.e., nepmucin/CD300g and autotaxin, in lymphocyte TEM.

The Ectoenzyme E-NPP3 Negatively Regulates ATP-Dependent Chronic Allergic Responses by Basophils and Mast Cells

“…E-NPP1 was shown to generate pyrophosphate through NTP hydrolysis and thereby inhibit bone mineralization (Hessle et al, 2002;Okawa et al, 1998). E-NPP2 acts as lysophospholipase-D, which hydrolyzes lysophosphatidylcholine into lysophosphatidic acid, thereby mediating several biologic responses such as lymphocyte transmigration and vascular development (Kanda et al, 2008;Umemoto et al, 2011;van Meeteren et al, 2006). In contrast to E-NPP1 and E-NPP2, whose functions are well characterized, the function of E-NPP3 (CD203c) remains undetermined despite its high expression in activated basophils.…”

Constitutive Lymphocyte Transmigration across the Basal Lamina of High Endothelial Venules Is Regulated by the Autotaxin/Lysophosphatidic Acid Axis

“…The entry of naive lymphocytes into LNs occurs exclusively at the high endothelial venules (HEVs), where lymphocytes go through a multistep adhesion cascade to selectively interact with HEVendothelial cells (ECs) and, finally, to extravasate from these blood vessels. Although this multistep adhesion cascade has been studied in detail (1,2), the precise molecular mechanism for lymphocyte egress from the HEVs (i.e., extravasation) remains unclear (3).…”

Expression Depression ofCD300LG-γin Human Pulmonary Carcinoma

“…(21) CD300LG has been found to be involved in lymphocyte adhesion, rolling, and TEM, which indicates that CD300LG might play important roles in antitumor effects of lymphocytes. (1,2,(4)(5)(6)(7) In the previous study, we have successfully generated a monoclonal antibody of human CD300LG-g. (9) In this study, we preliminarily explored the involvement of CD300LG in tumorigenesis, by comparing CD300LG-c expression between pulmonary carcinoma tissues and tumor-adjacent tissues at the mRNA and protein levels. Semiquantitative reverse transcription-PCR results showed that human CD300LG-c gene expression in pulmonary carcinoma tissues was dramatically lower than in tumor-adjacent tissues.…”

“…(1,2) Due to alternative splicing of the mucin domain, the following four isoforms are made: CD300LG-d (332aa, isoform CRA_a), CD300LG-g (298aa, isoform CRA_d), two CD300LG-a, CD300LG-a1 (233aa, isoform CRA_c), and CD300LG-a2 (222aa, isoform CRA_b) according to the amino acid difference in the C terminal.…”