Dendritic cells, T cells and lymphatics: dialogues in migration and beyond

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ScienceDirect Dendritic cells, T cells and lymphatics: dialogues in migration and beyond Marc Permanyer1, Berislav Bosˇnjak1 and Reinhold Fo¨rster Immune cells continuously recirculate through lymph vessels en route from peripheral tissues to the blood. Leuyte trafficking into and within lymph vessels is mediated by an interply with lymphatic endothelial cells (LECs). However, lymphatic vessels are much more than mere conduits for fluid and immune cell transport. Data accumulating during past several years indicate that LECs support T cell survival, induce tolerance to selfantigens, inhibit exaggerated T cell proliferation during immune response and maintain T cell memory. Reciprocally, leukocytes impact LEC biology: lymphatic vessel permeability depends on DCs while lymphocytes regulate LEC proliferation during inflammation. Altogether, these novel results provide important insights on intimate connections between LECs and leukocytes that contribute to the understanding of immune responses. Address Institute of Immunology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Corresponding author: Fo¨rster, Reinhold ([email protected]) 1 These authors contributed equally. Current Opinion in Immunology 2018, 53:xx–yy This review comes from a themed issue on Lymphangiogenesis: heterogeneity and function

entered the LN from the blood via high endothelial venules (HEV) and now continue their way towards the bloodstream. Of note, lymphocyte recirculation through lymph, as well as through blood, is influenced by a circadian rhythm, peaking during the day and being lowest during the night [4,5]. During inflammation, the number of leukocytes in afferent lymph increases, as well as the frequency of neutrophils and monocytes [1–3]. On the other hand, the number of leukocytes within the efferent lymph decreases within first 24 hours after infection due to a phenomenon called LN shut down that prevents egress of cells from inflamed LNs. After three to four days cell counts in the efferent lymph rise again due to increased efflux of newly proliferated lymphocytes [1– 3]. Results accumulating during recent years indicate that lymphatic vessels are not only highways for the transport of fluid and immune cells but that lymphatic endothelial cells (LECs) also affect the survival, activation and proliferation of DC and T cells. On the other hand, lymphocytes and DCs also impact on LEC proliferation during inflammation and have profound effects on lymphatic vessel integrity, respectively. In this review we will, therefore, discuss reciprocal interactions of LECs with DCs and T cells, the two main leukocyte populations present in the lymph (summarized in Figure 1).

Edited by S. Sozzani and M. Presta

LECs mediate DC and T cell migration through lymphatics https://doi.org/10.1016/j.coi.2018.05.004

DC entry into lymphatic capillaries

0952-7915/ã 2018 Published by Elsevier Ltd.

Intravital microscopy studies have provided detailed insights into the cellular processes directing DC migration into afferent lymphatics (for recent reviews see ref. [6–8]). It is well accepted that LECs-imprinted haptotactic gradients of the chemokine CCL21 attract DCs, which express the CCL21 receptor CCR7, towards lymphatic vessels [9]. Once tackled, transmigration across LECs also requires initial docking of DCs to CCL21 on LECs [10]. Interestingly, it has been recently shown that DCs do not encounter pre-immobilized CCL21 but trigger local CCL21 secretion from LECs [11], therefore stimulating their own transmigration through loose flaplike openings left between LECs [12]. LECs also direct leukocyte migration via atypical chemokine receptors (ACKRs) that internalize chemokines without transducing signals and therefore act as a sink for chemokines bound to them. ACKR2 on inflamed endothelial cells can selectively scavenge inflammatory, but not homeostatic chemokines such as CCL21 thus ensuring that only appropriate interactions of mature DCs with homeostatic chemokines occur at this stage [13]. Moreover, skin

Introduction To patrol the organism, leukocytes constantly migrate via blood and lymph between lymphoid organs and peripheral tissues. Cell turnover through the peripheral tissue is enormous: in humans and sheep every hour up to five million cells pass through the lymphatic vessels draining the lower part of the (hind) leg [1–3]. Under non-inflammatory conditions the majority of the cells present in the afferent, that is, lymph that drains from the periphery towards the first draining lymph node (LN), are T cells (up to 90%) and dendritic cells (DCs; up to 10%), accompanied by some neutrophils, B cells and monocytes [1–3]. The cell composition of the lymph changes after passing the draining LN. In this efferent lymph, as it is now called, primarily naı¨ve B and T cells are found that www.sciencedirect.com

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174 Lymphangiogenesis: heterogeneity and function

Figure 1

Summary of recently identified interactions between LECs and leucocytes that regulate immune responses during migration. (a) Leukocytes extravasate from peripheral tissues into lymphatic capillaries in a CCL21-dependent manner upon interaction with LECs [9,10]. DCs also use hyaluronan (HA) for binding to LYVE-1 expressed on LECs to enter lymph vessels in the skin [19]. (b) Lymphocytes roll in lymphatic capillaries in an integrin-dependent manner following CCL21 gradients, before they are passively carried away with the lymph flow in the afferent lymph vessels towards draining LN [21]. (c) ACKR4-mediated scavenging of CCL21 by LECs on the ceiling of LN subcapsular sinus (cLECs) shapes functional chemokine gradients that enhance DC translocation into LN parenchyma [36,37]. (d) S1P expression by LECs from LN cortical sinusoids regulates lymphocyte exit [39]. (e) Reciprocally, LECs can induce tolerance to self-antigens via direct presentation cross-presentation or of peripheral tissue antigens (PTA) in the context of MHC class I molecules [45–48] or by antigen transfer to the DCs for presentation in the context of MHC class II molecules [47]. (f) LECs can promote survival of naı¨ve T cells in LNs by expressing IL-7 and S1P [40,41,42] and prevent exaggerated T cell proliferation by releasing nitric oxide (NO) and indoleamine 2,3 dioxygenase (IDO) [53,54]. (g) Additionally, lymphatic permeability depends on the interaction of CCR7-expressing IFN regulatory factor 4-positive (IRF4+) dendritic cells with collecting vessels [63].

stromal cell-expressed ACKR4 mediates scavenging of CCL19 thus creating a chemokine gradient towards terminal lymphatics that can be efficiently followed by CCR7-expressing DCs [14]. Other molecules produced by LECs required for DC migration into lymphatics include podoplanin [15], semaphorins [16], galectin-1 [17], sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) and S1PR3 [18] and the lymphatic vessel endothelial protein 1 (LYVE-1) [19]. Specifically, DC use hyaluronan to adhere to LYVE-1 expressed on LECs and to transmigrate through the endothelial monolayer via LYVE-1-enriched ring-like structures surrounding the migrating DC [19] (Figure 1a). Within the lumen of Current Opinion in Immunology 2018, 53:173–179

lymphatic capillaries, DCs crawl towards collecting vessels by CCL21 chemokine gradients before falling into collecting vessels where cells are passively transported by lymph flow [20] (Figure 1b). T cell entry into lymphatic capillaries

In comparison to DCs, less is known about the mechanisms regulating T cell trafficking from peripheral tissues into afferent lymphatics. While naı¨ve T cells are restrained from the entry into the peripheral tissues, memory T cells represent the main cell type that recirculate between peripheral tissues and LN during noninflammatory, homeostatic conditions [1–3]. During www.sciencedirect.com

Cross talks between immune and lymphatic endothelial cells Permanyer, Bonjak and Fo¨rster 175

inflammation, activated T cells can also leave the inflamed tissue via afferent lymphatics and travel back to the LN [21]. Interestingly, in both steady-state and inflammatory conditions CD8+ T cells appear to egress from the skin less efficiently than CD4+ T cells [2,3,22]. The molecular events regulating T cell retention or exit from peripheral tissue are still largely unclear [23,24]. It is widely accepted that CCR7 mediates T cell exit from peripheral tissue [25,26] while S1PR1 regulates their retention [27]. In addition, several other molecules expressed on lymphatics have been reported to regulate lymphocyte migration, including macrophage mannose receptor [28], clever-1/stabilin-1 [29] and lymphotoxin receptor (LTbR) with the latter being specifically used by transmigrating T regs [30]. The molecular events regulating T cell entry into lymphatic vessels, however, have not been imaged until recently [21]. Using intravital microscopy it was shown that, in steady state, T cells actively crawl from tissue into lymphatic capillaries but are passively transported once they entered lymphatic collectors [21]. By contrast, under inflammatory conditions, T cells require interaction of LFA-1 with LECexpressed ICAM-1 to increase their speed in lymphatic capillaries [21], resembling the requisites previously found for DC transmigration during inflammation [31] (Figure 1b). Afferent lymph vessel DC and T cell entry into LNs

Cells travelling within the afferent lymph are drained into the LN subcapsular sinus (SCS), a space between LN capsule and cortex. The SCS enwraps the LN and merges into the medullary sinus from which lymph leaves the organ via efferent lymphatics. The SCS is further connected to the medullary sinus through cortical sinusoids and to high endothelial venules (HEV) of the T cell zone via fibroblastic reticular cell (FRC)-coated conduits. The latter serve as transport routes for small molecular weight molecules towards DCs residing next to HEV. Within the LN, LECs are subdivided according to their anatomical location [32] and expression of different markers including PD-L1, ICAM-1 and MAdCAM-1 in mice [33] and Prox1, LYVE1 and STAB2 in humans [34]. These subsets include (i) SCS-lining S-LECs, (ii) cortical sinusoidslining C-LECs and (iii) medullary sinus(oids)-lining MLECs. Differential expression of 685 genes including chemokines, adhesion molecules and growth factors between S-LECs and M-LECs [35] implies that divergent LEC populations have distinct functions in mediating lymphocyte trafficking. We have shown earlier that SLECs lining the ceiling of the SCS express ACKR4, thereby shaping CCL21 (and possibly CCL19) gradients that are important for DC immigration into the LN parenchyma [36,37] (Figure 1c). On the other hand, SLEC lining the SCS floor express plasmalemma vesicleassociated protein (PLVAP or MECA-32) that has been suggested to restrict lymphocyte entry into the LN by forming diaphragms in transendothelial channels [38]. If www.sciencedirect.com

not co-injected with DCs, naı¨ve T cells do not penetrate S-LECs but migrate from the medulla in a retrograde manner into the parenchyma using medullary sinusoids [8,37]. In the slow flowing lymph within the LN medullary sinus the migration pattern of T cells depends on the balance of expression of CCR7 and S1PR1 (reviewed in [39]). High concentration of S1P in lymph induces internalization S1PR1, allowing naı¨ve T cells to migrate towards CCR7 ligands expressed by stromal cells in the LN parenchyma. On the other hand, within the LN parenchyma CCR7 ligands induce CCR7 desensitization while S1PR1 gets re-expressed. Both events render T cells more sensitive towards S1P present in the lymph and thereby mediating their egress from the LN (Figure 1d). It remains to be determined whether other lymph-derived lymphocyte subtypes such as memory T cells, activated T cells or B cells can enter the lymph node parenchyma at all and, in case they do, whether they use direct (via the SCS floor) or indirect entry routes (via medullary sinusoids) LECs regulate T cell egress into efferent lymph

T cells emigrating from the LN parenchyma are collected in the medullary sinus and then drained into the efferent lymph vessel. As LN are organized in chains [36,37], cells exiting from the most distal LN in a chain will pass a series of LN before they eventually reach the thoracic duct and return into blood. For each LN in a chain, cells will presumably go through the same “decision process” of entering or bypassing that LN [8].

LECs regulate T cell survival and activation LECs promote T cell survival

Besides providing a framework for lymphocyte recirculation, LECs also support T cell survival during migration [40,41,42] (Figure 1f). LN LECs produce high amounts of IL-7 [41,42], a cytokine that provides anti-apoptotic signals to lymphocytes. In addition, group from Susan Schwab recently reported that S1P produced by LN LECs, apart from regulating lymphocyte exit from the LN, also promotes survival of naı¨ve T cells by supporting their mitochondrial function and thus providing cells with the energy for migration [40]. It will be interesting to find out whether S1P also affects the survival of other immune cell subsets, which is likely due to importance of S1P on DC functionality [18]. LECs present antigens

LECs also regulate T cell activation (reviewed recently in [43,44]). In homeostatic conditions, LN LECs express multiple peripheral tissue antigens (Figure 1e). These are presented in the context of MHC class I molecules together with high levels of PD-L1, which leads to PD-1 expression on CD8+ T cells and their subsequent ablation [45–47]. Moreover, LN LECs can scavenge lymph-borne antigens and cross-present them to CD8+ T cells, inducing their aberrant activation and exhaustion Current Opinion in Immunology 2018, 53:173–179

176 Lymphangiogenesis: heterogeneity and function

[48]. In contrast, it seems that LECs do not present selfantigens in the context of MHC class II molecules, but rather pass them to DCs to induce CD4+ T cell energy [47]. Altogether, these data indicate that steady-state LN LECs substantially contribute to the induction of peripheral T cell tolerance, as is already well described for liver sinusoidal endothelial cells [49]. In addition to the presentation of self-antigens, LN LECs have been reported to serve as antigen reservoirs for several weeks following vaccination or viral infection [50]. Similar to self-antigens, foreign antigens can also be handed over from LECs to migratory DCs for being presented to T cells [50,51], a process that might be important for maintenance of resident memory CD4+ T cells in the LN [52]. LECs regulate T cell proliferation during inflammation

Besides presenting antigens, cytokine-stimulated LECs can also directly inhibit T cell proliferation by releasing nitric oxide and indoleamine 2,3 dioxygenase [53,54] (Figure 1f). Moreover, TNFa-stimulated LECs decrease CD86 expression on immature or TNFa-stimulated DCs dampening their ability to further stimulate T cell proliferation [55]. These data suggest that LECs might interfere with T cell activation during ongoing immune response, thereby counteracting potentially overshooting immune responses.

DCs and lymphocytes regulate LEC functions

of collecting lymphatic vessels is regulated by the interaction of CCR7-expressing IRF4+ DCs with LECs [63] (Figure 1g). Moreover, sampling of lymph-borne antigen by adipose tissue DCs induces their CCR7-dependent recruitment into skin-draining LN [62]. This finding suggests that collecting lymphatic vessel leakage would reinforce an ongoing immune response by supplementing the draining LN with an extra pool of antigen-bearing DCs [62]. Moreover, these DCs support secondary immune responses of antigen-specific T cells that reside in the adipose tissue and provide protection against recurrent infections [62,64]. By contrast, others have reported that gut bacterial infection can lead to the formation of highly permeable lymph vessels that redirect DCs into mesenteric adipose tissue and prevent them from migrating to LNs, thus compromising mucosal immune responses [65]. Similarly, lymphocyte aggregates resembling tertiary lymphoid organs (TLOs) have been recently identified aligned with collecting lymphatic vessels in Crohns disease mesentery [66]. Furthermore, these TLOs-like structures might potentially compromise lymphatic vessel integrity raising the possibility that remodelling of lymphatic vessels and thus impaired lymph drainage could affect the course of the disease [66]. Therefore, lymph vessel permeability is a double-edged sword that can reinforce but also interfere with immune responses. Clearly, more studies are needed to understand the contribution of lymphatic vessel permeability to autoimmune and inflammatory diseases.

Lymphoangiogenesis during inflammation

At the sites of tissue inflammation macrophages and granulocytes secrete vascular endothelial growth factors (VEGF)-A and (VEGF)-C. These induce LEC sprouting, migration, proliferation and lymphatic vessels growth that are all required to accommodate the increase in leukocyte migration and tissue drainage [56]. Similarly, LECs in the inflamed LN expand rapidly to lodge increased leukocyte numbers. The main VEGF producing cells in the LN are B cells in mice [57] and CD11c+ DCs in humans [58]. On the other hand, cytokines secreted by helper T cells, including IFN-ɣ [59], IL-17A [60], IL-4 and IL-13 [61], counterbalance the pro-lymphoangiogenic effects of VEGFs. Establishment of productive T cell immune response, therefore, appears to provide an auto-inhibitory loop that restricts further lymphoangiogenesis and eventually leads to lymph vessel regression during inflammation resolution. Different aspects of lymphoangiogenesis have been reviewed in detail by others in this issue of Current Opinions in Immunology. DCs regulate lymphatic vessel integrity

Recent reports indicate that, due to the inherent permeability of lymphatic vessels, soluble antigens and other lymph-borne proteins extravasate into the surrounding adipose tissue where they are taken up by macrophages and DCs [62]. It has been shown that the basal integrity Current Opinion in Immunology 2018, 53:173–179

Conclusions Lymphatic vessels not only provide the avenues for immune cell re-circulation, but also actively contribute to shape and regulate immune responses. LECs coordinate DC and T cell interaction, activate or suppress immunity and promote immune cell survival. Vice versa, immune cells are important players in regulating collecting lymph vessel integrity and lymphatic vessel density in LN. These central features bring lymph vessels from being seen as “simple conduits” to attractive target structures for the treatment of chronic inflammatory diseases. Further advances in immune-imaging, providing improved intravital imaging tools as well as transgenic mice expressing photo-convertible proteins, will help to increase our understanding of cellular and molecular events that regulate immune cell re-circulation between blood, tissue and lymphoid organs. Moreover, a closer examination of the diversity of LECs using new genomic approaches will also provide better understanding of their origin and function. In sum, we are just starting to understand the complexity of how and why LECs and immune cells interact with each other and how this can be exploited to interfere with undesired immune responses and dysfunctional lymphatics. www.sciencedirect.com

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Conflict of interest statement Nothing declared.

Acknowledgements We regret that we not always could adequately cite the work of our colleagues due to space limitations. We would like to thank Swantje Hammerschmidt and Gu¨nter Bernhardt for critical reading of the manuscript. The work of R.F. is supported by Deutsche Forschungsgemeinschaft (DFG) [grant numbers SFB900-B1, SFB738-B5, KFO250, FO334/5-1], the European Research Council (ERC) [advanced grant number 322645], and the Government of Lower Saxony [N-RENNT, BioFabrication].

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Current Opinion in Immunology 2018, 53:173–179