A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes

Preferential homing of naive lymphocytes to secondary lymphoid organs is thought to involve the action of chemokines, yet no chemokine has been shown to have either the expression pattern or the activities required to mediate this process. Here we show that a chemokine represented in the EST database, secondary lymphoid-tissue chemokine (SLC), is expressed in the high endothelial venules of lymph nodes and Peyer’s patches, in the T cell areas of spleen, lymph nodes, and Peyer’s patches, and in the lymphatic endothelium of multiple organs. SLC is a highly efficacious chemoattractant for lymphocytes with preferential activity toward naive T cells. Moreover, SLC induces firm adhesion of naive T lymphocytes via β2 integrin binding to the counter receptor, intercellular adhesion molecule-1, a necessary step for lymphocyte recruitment. SLC is the first chemokine demonstrated to have the characteristics required to mediate homing of lymphocytes to secondary lymphoid organs. In addition, the expression of SLC in lymphatic endothelium suggests that the migration of lymphocytes from tissues into efferent lymphatics may be an active process mediated by this molecule.     

Constitutively active ezrin increases membrane tension, slows migration, and impedes endothelial transmigration of lymphocytes in vivo in mice

ERM (ezrin, radixin moesin) proteins in lymphocytes link cortical actin to plasma membrane, which is regulated in part by ERM protein phosphorylation. To assess whether phosphorylation of ERM proteins regulates lymphocyte migration and membrane tension, we generated transgenic mice whose T-lymphocytes express low levels of ezrin phosphomimetic protein (T567E). In these mice, T-cell number in lymph nodes was reduced by 27%. Lymphocyte migration rate in vitro and in vivo in lymph nodes decreased by 18% to 47%. Lymphocyte membrane tension increased by 71%. Investigations of other possible underlying mechanisms revealed impaired chemokine-induced shape change/lamellipod extension and increased integrin-mediated adhesion. Notably, lymphocyte homing to lymph nodes was decreased by 30%. Unlike most described homing defects, there was not impaired rolling or sticking to lymph node vascular endothelium but rather decreased migration across that endothelium. Moreover, decreased numbers of transgenic T cells in efferent lymph suggested defective egress. These studies confirm the critical role of ERM dephosphorylation in regulating lymphocyte migration and transmigration. Of particular note, they identify phospho-ERM as the first described regulator of lymphocyte membrane tension, whose increase probably contributes to the multiple defects observed in the ezrin T567E transgenic mice.     

Autonomous T cell trafficking examined in vivo with intravital two-photon microscopy

The recirculation of T cells between the blood and secondary lymphoid organs requires that T cells are motile and sensitive to tissue-specific signals. T cell motility has been studied in vitro, but the migratory behavior of individual T cells in vivo has remained enigmatic. Here, using intravital two-photon laser microscopy, we imaged the locomotion and trafficking of naive CD4(+) T cells in the inguinal lymph nodes of anesthetized mice. Intravital recordings deep within the lymph node showed T cells flowing rapidly in the microvasculature and captured individual homing events. Within the diffuse cortex, T cells displayed robust motility with an average velocity of approximately 11 microm x min(-1). T cells cycled between states of low and high motility roughly every 2 min, achieving peak velocities >25 microm x min(-1). An analysis of T cell migration in 3D space revealed a default trafficking program analogous to a random walk. Our results show that naive T cells do not migrate collectively, as they might under the direction of pervasive chemokine gradients. Instead, they appear to migrate as autonomous agents, each cell taking an independent trafficking path. Our results call into question the role of chemokine gradients for basal T cell trafficking within T cell areas and suggest that antigen detection may result from a stochastic process through which a random walk facilitates contact with antigen-presenting dendritic cells.     

Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis

OBJECTIVE: Clonal populations of CD4+,CD28- T cells accumulating in rheumatoid arthritis functionally resemble end-differentiated, nondividing, short-lived effector memory cells that reside in peripheral tissues. We undertook this study to examine the tissue niche for CD4+,CD28- T cells and the signals regulating their survival and tissue homing patterns. METHODS: Chemokine receptor expression on CD4+,CD28- T cell clones and peripheral blood lymphocytes was assessed by multicolor cytometry. In vitro chemotaxis and transendothelial migration were examined in a Transwell system. In vivo tissue-homing patterns were established by adoptively transferring fluorescence-labeled T cell clones into SCID mice engrafted either with rheumatoid synovium or with human lymph nodes. RESULTS: CD4+,CD28- T cell clones adoptively transferred into human tissue-SCID mouse chimeras infiltrated rheumatoid synovium but preferentially homed to lymph nodes. Such T cells coexpressed the chemokine receptors CCR7, CCR5, and CXCR4 and migrated in response to both inflammatory chemokines (CCL5) and homing chemokines (CXCL12). T cell receptor crosslinking abrogated chemotactic responsiveness. In contrast, interleukin-12 stimulation induced the up-regulation of CCR5 and a shift in the in vivo homing pattern away from the lymph nodes toward the inflamed synovium. CONCLUSION: CD4+,CD28- T cells resemble both short-lived effector memory cells and long-lived central memory cells, and they find a niche both in inflamed synovium and in lymph nodes. Nonspecific cytokine stimulation, not antigen recognition, triggers the transition from the lymph node to the synovium. By maintaining CCR7 expression, these end-differentiated T cells can home to lymphoid organs, enhance their survival, support clonal expansion, and perpetuate autoreactivity.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Shigella impairs T lymphocyte dynamics in vivo

The Gram-negative enteroinvasive bacterium Shigella flexneri is responsible for the endemic form of bacillary dysentery, an acute rectocolitis in humans. S. flexneri uses a type III secretion system to inject effector proteins into host cells, thus diverting cellular functions to its own benefit. Protective immunity to reinfection requires several rounds of infection to be elicited and is short-lasting, suggesting that S. flexneri interferes with the priming of specific immunity. Considering the key role played by T-lymphocyte trafficking in priming of adaptive immunity, we investigated the impact of S. flexneri on T-cell dynamics in vivo. By using two-photon microscopy to visualize bacterium–T-cell cross-talks in the lymph nodes, where the adaptive immunity is initiated, we provide evidence that S. flexneri, via its type III secretion system, impairs the migration pattern of CD4⁺ T cells independently of cognate recognition of bacterial antigens. We show that bacterial invasion of CD4⁺ T lymphocytes occurs in vivo, and results in cell migration arrest. In the absence of invasion, CD4⁺ T-cell migration parameters are also dramatically altered. Signals resulting from S. flexneri interactions with subcapsular sinus macrophages and dendritic cells, and recruitment of polymorphonuclear cells are likely to contribute to this phenomenon. These findings indicate that S. flexneri targets T lymphocytes in vivo and highlight the role of type III effector secretion in modulating host adaptive immune responses.     

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

Aims/hypothesis An important prerequisite for the initiation of pancreatic islet inflammation is the recruitment of pathogenic T cells. We investigated the in vivo migration patterns of human islet-reactive T cell clones after transfer into compromised hosts.Methods NOD-scid mice were injected with a mixture of human autoreactive T cells and antigen-presenting cells. Survival and migration of T cells was analysed by fluorescence-activated cell sorter and immunohistochemical analysis of various tissues.Results Autoreactive T cells and antigen-presenting cells survived at least 14 days in vivo and accumulated in spleen, pancreatic tissue and pancreas draining lymph nodes, but not elsewhere, as early as 4 days after transfer. This homing was dependent on co-injection of human antigen-presenting cells loaded with autoantigen. Finally, we found that this process is enhanced by streptozotocin treatment. Streptozotocin treatment did not affect the constitutive homing to pancreas draining lymph nodes. Histological analysis of pancreatic tissue sections showed some autoreactive T cells around the islets of Langerhans, comparable to early peri-islet insulitis. However, the majority of pancreas-infiltrating T cells accumulated around blood vessels in the exocrine pancreas. All T cell clones expressed the chemokine receptor CXCR3 that is associated with homing to insulitic lesions in men and mice.Conclusions/interpretation Our study provides the first evidence of in vivo accumulation in pancreatic tissue of islet-reactive T cells derived from type 1 diabetic patients. The fact that such T cells do not penetrate islets is in line with the concept that additional factors may be required for the entry of T cells into inflamed islets to become diabetogenic.     

HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signaling

The Nef protein of HIV-1 facilitates viral replication and disease progression in vivo. Nef disturbs the organization of immunological synapses between infected CD4(+) T lymphocytes and antigen-presenting B-lymphocytes to interfere with TCR proximal signaling. Paradoxically, Nef enhances distal TCR signaling in infected CD4(+) T lymphocytes, an effect thought to be involved in its role in AIDS pathogenesis. Using quantitative confocal microscopy and cell fractionation of Nef-expressing cells and HIV-1-infected primary human T lymphocytes, we found that Nef induces intracellular compartmentalization of TCR signaling to adjust TCR responses to antigenic stimulation. Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi network (TGN), thereby preventing the recruitment of active Lck to the immunological synapse after TCR engagement and limiting signal initiation at the PM. Instead, Nef triggers Lck-dependent activation of TGN-associated Ras-Erk signaling to promote the production of the T lymphocyte survival factor IL-2 and to enhance virus spread. Overexpression of the Lck PM transporter Unc119 restores Nef-induced subversions of Lck trafficking and TCR signaling. Nef therefore hijacks Lck sorting to selectively activate TGN-associated arms of compartmentalized TCR signaling. By tailoring T-lymphocyte responses to antigenic stimulation, Nef optimizes the environment for HIV-1 replication.     

Enhanced and aberrant T cell trafficking following total body irradiation: a gateway to graft‐versus‐host disease?

Pre‐transplant conditioning regimens play a major role in triggering graft‐versus‐host disease (GVHD). This study investigated the effect of irradiation on donor T cell trafficking to lymphoid and non‐lymphoid tissues by comparing the migration of carboxy‐fluorescein diacetate succinimidyl ester‐labelled, naïve donor T lymphocytes in vivo in irradiated and non‐irradiated syngeneic mice recipients. Recruitment of adoptively transferred naïve T cells to secondary lymphoid organs was increased in irradiated mice and naïve T cells also aberrantly localized to non‐lymphoid tissues. Irradiation also induced aberrant effector memory T cell migration into lymph nodes and their localization to homing‐privileged non‐lymphoid sites, such as the gut. The presence of a minor histocompatibility mismatch further enhanced the aberrant accumulation of T cells in both lymphoid and non‐lymphoid tissue, whilst their migratory pattern was not modified as compared to fully matched irradiated recipients. These effects correlated with decreased permeability of, and the secretion of chemotactic factors by the endothelium. Our findings are consistent with the possibility that excessive, dysregulated extravasation of T cells induced by irradiation promotes the development of GVHD.     

Heterologous cells cooperate to augment stem cell migration,homing, and engraftment

T-lymphocyte depletion of bone marrow grafts compromises engraftment, suggesting a facilitating mechanism provided by the T cells that has been shown to associate with CD8(+) but not CD4(+) T cells. Explanations for this phenomenon have focused on immune targeting of residual host cells or cytokine production. We provide evidence for an alternative mechanism based on cooperative effects on cell motility. We observed that engraftment of CD34(+) cells in a beta(2)-microglobulin-deficient nonobese diabetic/severe combined immunodeficiency (beta(2)m(-/-) NOD/SCID) mouse model paralleled clinical observations in humans, with an enhancing effect noted from the addition of CD8(+) cells but not CD4(+) cells. This correlated with CD8(+) augmentation of CD34(+) cell homing to the bone marrow in vivo and CD8(+) cell-associated increases of CD34(+) cell transmigration through a bone marrow endothelial cell line in vitro. The cooperative interaction was not sensitive to brefeldin A inhibition of protein secretion. However, cytochalasin D-induced inhibition of CD8(+) cytoskeletal rearrangements abrogated CD34(+) transendothelial migration and impaired CD34(+) cell homing in vivo. CD8(+) cells did not migrate in tandem with CD34(+) cells or alter endothelial barrier integrity; rather, they affected phosphotyrosine-mediated signaling in CD34(+) cells in response to the chemokine stromal derived factor-1alpha (SDF-1alpha). These data demonstrate cell-cell cooperativity between different cell types in mediating chemotactic events and provide one potential explanation for the clinically observed effect of CD8(+) cells on bone marrow transplantation. This modification of cell migration by neighboring cells provides broad possibilities for combinatorial effects between cells of different types to influence cell localization.     

Ly-6C regulates endothelial adhesion and homing of CD8+ T cells by activating integrin-dependent adhesion pathways

Ly-6C belongs to the Ly-6 family of glycosyl phosphatidylinositol-anchored surface glycoproteins and is expressed on a subset of mature CD8⁺ T cells. Ly-6C ligation can mediate T cell activation and causes interleukin 2 secretion in cytolytic T cell clones. We characterize herein a new mAb 1G7.G10 against Ly-6C that recognizes an epitope involved in lymphocyte adhesion and in lymphocyte homing. Pretreatment of lymph node lymphocytes and of purified CD8⁺ T cells (but not of lymphocytes depleted of CD8⁺ T cells) with 1G7.G10 reduced their in vitro binding to lymph node high endothelial venules by 28% and 34%, respectively. This effect was bypassed by cross-linking Ly-6C molecules with 1G7.G10 and a second-step antibody. The in vivo homing of (donor) CD8⁺ T lymphocytes to lymph nodes was reduced by Ly-6C blocking with 1G7.G10 (whole antibody) or with its fragments [F(ab) or F(ab)₂] by 20% or by 32% and 48%, respectively. Cross-linking of Ly-6C in vitro induced very late antigen-4 and lymphocyte function-associated antigen 1-mediated aggregation of CD8⁺ T cells, suggesting that ligand binding to Ly-6C leads to activation of integrins. This activation may facilitate homing of Ly-6C⁺ CD8⁺ T cells in vivo.     

Peyer’s patch organogenesis is intact yet formation of B lymphocyte follicles is defective in peripheral lymphoid organs of mice deficient for tumor necrosis factor and its 55-kDa receptor

Targeted inactivation of genes in the tumor necrosis factor (TNF)/lymphotoxin (LT) ligand and receptor system has recently revealed essential roles for these molecules in lymphoid tissue development and organization. Lymphotoxin-αβ (LTαβ)/lymphotoxin-β receptor (LTβ-R) signaling is critical for the organogenesis of lymph nodes and Peyer’s patches and for the structural compartmentalization of the splenic white pulp into distinct B and T cell areas and marginal zones. Moreover, an essential role has been demonstrated for TNF/p55 tumor necrosis factor receptor (p55TNF-R) signaling in the formation of splenic B lymphocyte follicles, follicular dendritic cell networks, and germinal centers. In contrast to a previously described essential role for the p55TNF-R in Peyer’s patch organogenesis, we show in this report that Peyer’s patches are present in both TNF and p55TNF-R knockout mice, demonstrating that these molecules are not essential for the organogenesis of this lymphoid organ. Furthermore, we show that in the absence of TNF/p55TNF-R signaling, lymphocytes segregate normally into T and B cell areas and a normal content and localization of dendritic cells is observed in both lymph nodes and Peyer’s patches. However, although B cells are found to home normally within Peyer’s patches and in the outer cortex area of lymph nodes, organized follicular structures and follicular dendritic cell networks fail to form. These results show that in contrast to LTαβ signaling, TNF signaling through the p55TNF-R is not essential for lymphoid organogenesis but rather for interactions that determine the cellular and structural organization of B cell follicles in all secondary lymphoid tissues.     

Anti-inflammatory effects of an inflammatory chemokine: CCL2 inhibits lymphocyte homing by modulation of CCL21-triggered integrin-mediated adhesions

Our studies focus on the pathways that restrict homing of specific subsets of immune cells, and thereby fine-tune the immune response at specific lymphoid and peripheral tissues. Here, we report that CCL2 (at picomolar [pM] levels) renders both murine and human T cells defective in their ability to develop CCR7-triggered activation of LFA-1- and LFA-1-mediated adhesion strengthening to endothelial ICAM-1 both in vitro and in vivo. CCL2 also attenuated lymphocyte chemotaxis toward lymph node chemokines. Consequently, low-dose CCL2 inhibited lymphocyte homing to peripheral lymph nodes but did not affect lymphocyte trafficking through the spleen. Impaired homing of lymphocytes to peripheral lymph nodes resulted in attenuated progression of both asthma and adjuvant arthritis. Thus, pM levels of circulating CCL2 can exert global suppressive effects on T-cell trafficking and differentiation within peripheral lymph nodes, and may be clinically beneficial as an anti-inflammatory agent.     

A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+ CD3- cells to colonize lymph nodes.

IN adult mice, the dominant adhesion molecules involved in homing to lymph nodes are L-selectin homing receptors on lymphocytes and the peripheral lymph node addressins on specialized high endothelial venules. Here we show that, from fetal life through the first 24 hr of life, the dominant adhesion molecules are the mucosal addressin MAdCAM-1 on lymph node high endothelial venules and its counterreceptor, the Peyer's patch homing receptor, integrin alpha 4 beta 7 on circulating cells. Before birth, 40-70% of peripheral blood leukocytes are L-selectin-positive, while only 1-2% expresses alpha 4 beta 7. However, the fetal lymph nodes preferentially attract alpha 4 beta 7-expressing cells, and this can be blocked by fetal administration of anti-MAdCAM-1 antibodies. During fetal and early neonatal life, when only MAdCAM-1 is expressed on high endothelial venules, an unusual subset of CD4 + CD3- cells, exclusively expressing alpha 4 beta 7 as homing receptors, enters the lymph nodes. Beginning 24 hr after birth a developmental switch occurs, and the peripheral node addressins are upregulated on high endothelial venules in peripheral and mesenteric lymph nodes. This switch in addressin expression facilitates tissue-selective lymphocyte migration and mediates a sequential entry of different cell populations into the lymph nodes.     

Hypothesis: lymphocyte trafficking in inflammatory rheumatic disease. A role for receptor mediated homing

The entry of lymphocytes into normal lymph nodes occurs principally after their passage across postcapillary high endothelial venules. Nonlymphoidal tissues do not normally express high endothelial venules; however, in inflammatory rheumatic diseases associated with prominent lymphocyte accumulation (e.g., rheumatoid synovium), high endothelial venule-like structures are found and may facilitate local lymphocyte traffic. In mouse and man there are lymphocyte surface membrane homing receptors which determine lymphocyte binding to acceptor sites on lymph node high endothelial venules. The migration of lymphocytes from the circulation into inflamed nonlymphoidal tissues may be controlled by similar homing receptor mediated mechanisms.     

The Migratory Properties of Indium-111 Oxine Labelled Lymphocytes in Patients with Chronic Lymphocytic Leukaemia

S ummary . These studies describe the application of a new method for following the migration of autologous lymphocytes in normal subjects and patients with chronic lymphocytic leukaemia (CLL). There is evidence that Indium 111 oxine is a reliable radioactive cell label for in vivo studies of lymphocyte traffic in man. In normal subjects, where 60-70% of the lymphocytes labelled are T cells, the results are different from those of previous workers. The lymphocytes leave the blood initially but later return to it. It is believed that this is due to the reappearance of cells which at first entered the spleen. It is suggested that the difference between these data and those of Hersey (1971) is due to the failure of lymphocytes in the latter studies to return to the blood after primary migration. In CLL no such reappearance in the blood is seen and the lymphocytes do not leave the spleen in significant numbers over 48 h. This suggests that CLL B cells either do not recirculate through spleen or that their transit time is greater than 48 h. Bone marrow localization in CLL patients is greater than in the normal subjects, suggesting that either a larger proportion of the neoplastic B lympliocytes enter this compartment or their transit time through it is longer than the transit time of a normal T cell predominant population. Localization in normal-sized lymph nodes in patients with CLL is less than that in the lymph nodes of normal subjects. This may possibly be explained by the greater propensity of T lymphocytes to enter lymph nodes than B lymphocytes, or by the altered migratory properties of CLL B lymphocytes as compared with normal B cells.     

In vitro analysis of the homing properties of human lymphocytes: developmental regulation of functional receptors for high endothelial venules

Circulating lymphocytes leave the blood by binding to specialized high endothelial cells lining postcapillary venules in lymphoid organs or sites of chronic inflammations, migrating through the vessel wall into the surrounding tissue. The capacity of lymphocytes to recognize and bind to high endothelial venules (HEVs) is thus central to the overall process of lymphocyte traffic and recirculation. We show that viable human lymphocytes bind selectively to HEVs in frozen sections of normal human lymph nodes, thus defining a simple in vitro model for the study of human lymphocyte homing properties. Optimal conditions for the quantitative analysis of lymphocyte-HEV interaction are described. Furthermore, by using this assay, we demonstrate that the ability of human lymphocyte populations to bind to HEVs parallels their presumed migratory status in vivo. Thus, thymocytes and bone marrow cells, which are sessile in vivo, bind poorly to HEVs in comparison with mature circulating lymphocytes in peripheral blood or in peripheral lymphoid tissues. These results indicate that HEV-binding ability is a regulated property of mature lymphocytes and, as demonstrated previously in animal models, probably plays a fundamental role in controlling lymphocyte traffic in humans. The in vitro model of lymphocyte-HEV interaction thus provides a unique means to assay the migratory properties of normal and neoplastic human lymphocyte subsets, to analyze the role of lymphocyte traffic mechanisms in normal and pathologic inflammatory reactions, and to define some of the molecular mechanisms responsible for the control of lymphocyte migration and positioning in humans.     

Ligation of the CD4 receptor induces activation-independent down-regulation of L-selectin.

Lymphocyte circulation plays an important role in the generation of a specific immune response. Mature lymphocytes continuously circulate between blood and lymph, entering the lymphoid tissue via high endothelial venules. Trafficking across high endothelial venules of peripheral lymph nodes (PLN) depends on the expression of L-selectin. It has been shown that L-selectin is rapidly cleaved from the surface by a metalloproteinase after in vitro activation. Here, we show that ligation of CD4, without ligation of the T cell receptor for antigen, causes down-regulation of L-selectin on T helper cells. This down-regulation is caused by proteolytic cleavage by a metalloproteinase and is reversible by the addition of hydroxamic acid-based metalloproteinase inhibitors. We show that in vivo down-regulation of L-selectin in huCD4tg mice by mAb reduces the homing of lymphocytes to PLN in adoptive transfer experiments. Because CD4 is a coreceptor for HIV-1, the down-regulation of L-selectin induced by CD4 ligation could play a role in the pathogenesis of AIDS. We provide evidence that CD4 ligation by HIV-1 induces metalloproteinase-dependent L-selectin down-regulation. Reduced levels of L-selectin expression might contribute to immune deficiency in individuals infected with HIV by inhibiting T cell redistribution and decreasing the probability of an encounter between specific lymphocytes and viral antigens in PLN.     

Selective endothelial binding of interleukin-2-dependent human T-cell lines derived from different tissues.

The ability of lymphocytes to recognize and bind to high endothelial venules (HEVs) is essential for lymphocyte migration from the blood into lymphoid tissues and into sites of inflammation. Endothelial cell binding capacity also critically determines the clinical usefulness of T-cell lines and clones in immunotherapy. In the present study, interleukin-2-dependent T-cell lines were derived from the blood, lamina propria of the gut, inflamed synovium, synovial fluid, and peripheral lymph nodes. After 3-8 weeks of culture, the expression of homing-associated molecules and binding to mucosal, synovial, and peripheral lymph node HEVs were analyzed. Cell lines derived from the blood and mucosal sites bound significantly better to mucosal and synovial HEVs than to peripheral lymph node HEVs. Three out of seven synovial T-cell lines showed preferential binding to synovial HEVs, whereas the rest bound almost equally well to synovial and mucosal HEVs. T-cell lines from peripheral lymph nodes bound preferentially to lymph node HEVs despite the lack of L-selectin (the peripheral lymph node homing receptor). Expression of the known homing-associated molecules did not predict the HEV-binding specificity of these lines. Importantly, two cell lines bound well to synovial venules, but poorly, if at all, to mucosal or peripheral lymph node HEVs, supporting the concept that synovial-specific HEV recognition mechanisms exist. In conclusion, the tissue origin of T-cell lines critically determines their selectivity for endothelial cell recognition, and besides the known "homing receptors," other molecules may also mediate tissue-specific HEV-binding of interleukin-2-activated T cells.     

Emerging role of chemokine receptor 7 in atherosclerosis

The CC chemokine receptor 7 (CCR7) and its ligands CCL19 and CCL21 essentially contribute to both immunity and tolerance by directing T cells and antigen-presenting dendritic cells (DCs) to and within lymph organs. In the pathogenesis of atherosclerosis, the accumulation of cholesterol in the subendothelial space of the vessel wall represents the initial step of plaque development in which DCs acquire and process low-density lipoprotein cholesterol as antigen in the vessel wall and then migrate to draining lymph nodes and present this antigen to naive T cells. Deletion of CCR7 receptor in murine atherosclerosis not only results in a reduced atherosclerotic plaque content but also leads to a disturbed entry and exit of T cells within the inflamed vessel wall. These observations are consistent with the notion that CCR7-dependent T cell priming in secondary lymphoid organs and CCR7-dependent recirculation of T cells between secondary lymphoid organs and inflamed tissue is pivotal for atherosclerotic plaque development and may represent an interesting target for innovative immune-modulatory therapy.