{'fraction_non_alphanumeric': 0.021922813427723224, 'fraction_numerical': 0.005709065996802923, 'mean_word_length': 5.697247706422019, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Editorial: In‐and‐out blood vessels: new insights into T cell reverse transmigration

Leukocyte trafficking is governed by bidirectional movements toward and away from chemotactic agents usually represented by chemokines. Chemotaxis or chemoattraction is defined as an active movement in response to chemokinetic agents. Reverse transmigration, also known as fugetaxis, intravasation, or chemorepulsion, is the active movement of leukocytes away from chemoattractants [1, 2]. Chemotaxis and reverse transmigration are unrelated to chemokinesis, which represents random cell movement in response to a chemical stimulus in the absence of a gradient. Leukocyte chemotaxis plays a pivotal role in physiological and pathological processes such as homing of the immune cells in lymphoid organs and their accumulation at sites of inflammation or tissue injury. So far, reverse transmigration has been shown to be involved in trafficking of leukocytes from the bone marrow to the vasculature and lymphocyte egress from lymphoid (e.g., thymus) and hematopoietic organs. Furthermore, leukocyte reverse transmigration has been proposed to play a critical role whenever leukocytes are repelled from specific sites, e.g., establishment of immune-privileged niches and immune evasion operated by viruses and tumor cells [3]. Leukocyte trafficking is controlled by interactions between leukocytes and endothelial cells and involves different steps: leukocyte rolling, firm adhesion to the endothelium mediated by integrin activation, and diapedesis [4]. Among the chemotactic factors involved in leukocyte trafficking, four chemokines have been demonstrated to induce arrest of rolling leukocytes under flow condition: CXCL12, CCL19, CCL20, and CCL21 [4]. Butcher and co-workers [5] proposed a multistep navigation model of leukocyte trafficking, whereby leukocytes navigate through a complex chemoattractant field by migrating in a step-by-step manner in response to one agonist from another. In this way, the ultimate position of navigating leukocytes is determined by the array of receptors they express and the chemoattractant gradients they encounter. A critical step of leukocyte trafficking is TEM, a process tightly regulated by chemokine gradients across the endothelium, and the presence of shear forces [6]. Chemokines play a pivotal role in leukocyte extravasation by promoting firm adhesion of leukocytes to vascular endothelium and subsequent diapedesis. These events take place under conditions of hemodynamic shear, which represents a fundamental component of all interactions between lymphocytes and endothelial cells. Initially, several studies of leukocyte TEM have been performed by using the well-known transwell/Boyden chamber, which measures the number of leukocytes migrated through a membrane or an endothelial layer in response to chemokines dispensed in the lower chamber under static conditions. The main limitation of this system is the absence of hemodynamic shear. Sackstein and co-workers [7] developed a novel TEM chamber mimicking the physiological events of leukocyte migration and in particular, the presentation of chemokines localized in an apical and a subendothelial zone of an endothelial monolayer. In particular, subendothelial CCL5 was shown to induce migration of a small proportion of T cells through HUVEC under static and flow conditions. Apical CXCL12 synergized with subendothelial CCL5 to stimulate T cell TEM under shear stress but not static conditions. Interestingly, shear stress induced extensive pseudopodial protrusion within junctions and in this way, facilitated transient T cell retention in the endothelial layer [7]. Another important phase of T cell migration is reverse transmigration, whereby cells leave tissues and enter the circulation. Although reverse transmigration has been investigated in different physiological [8] and histological [9] studies, little is known about the molecules regulating it. In the elegant study published in this issue of the Journal of Leukocyte Biology, Sackstein and co-workers describe a novel transwellbased flow chamber allowing real-time modulation of chemokines dispensed in the apical and subendothelial compartments of a HUVEC monolayer. Their results show that apical CXCL12 induced T cell TEM, but alteration of perivascular chemokine gradient postTEM with the introduction of varying