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

Gunn, Michael D.; Tangemann, Kirsten; Tam, Carmen; Cyster, Jason G.; Rosen, Steven D.; Williams, Lewis T.

doi:10.1073/pnas.95.1.258

Cited by 888 publications

(765 citation statements)

References 41 publications

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“…Of note, this synergism occurs also in the opposite direction: CCL7 synergizes with CCL19 and CCL21 on CCR7-transfected cells as well as on mature dendritic cells, as we previously described [9]. A meeting place of both homeostatic and inflammatory chemokines is HEV where CCL19 and CCL21 are both expressed [26], and CCL2 and CCL7 [20,42] are transported from inflamed tissue to trigger arrest of rolling monocytes [32]. Therefore, the CCR7 and the CCR2 agonists meet the criteria to be at the same place and at the same time to enhance the migration of CCR2 1 cells in vivo.…”

supporting

confidence: 51%

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Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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The migration of monocytes to sites of inflammation is largely determined by their response to chemokines. Although the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how cells integrate the messages provided by different chemokines that are concomitantly produced in physiological or pathological situations in vivo. We present evidence for one regulatory mechanism of human monocyte trafficking. Monocytes can integrate stimuli provided by inflammatory chemokines in the presence of homeostatic chemokines. In particular, migration and cell responses could occur at much lower concentrations of the CCR2 agonists, in the presence of chemokines (CCL19 and CCL21) that per se do not act on monocytes. Binding studies on CCR2 1 cells showed that CCL19 and CCL21 do not compete with the CCR2 agonist CCL2. Furthermore, the presence of CCL19 or CCL21 could influence the degradation of CCL2 and CCL7 on cells expressing the decoy receptor D6. These findings disclose a new scenario to further comprehend the complexity of chemokinebased monocyte trafficking in a vast variety of human inflammatory disorders.Key words: Chemokine receptors . Chemokines . Monocytes . Synergism IntroductionConcomitant exposure to multiple chemokines, the key controllers of several immune cell functions [1], can result in enhancement of immune responses. Only recently, a broad phenomenon known as ''chemokine synergism'' has been identified [2][3][4][5][6][7][8][9][10]. Cells expressing two or more chemokine receptors, in the presence of the selective agonists, can amplify their response [2][3][4][5][6]11]. The responses mediated by low agonist concentrations can be powerfully enhanced by non-ligand chemokines in cells that do not bear the second chemokine receptor [7][8][9]. Using different biochemical approaches, these studies demonstrated that CC and CXC chemokines form heteromeric complexes, which could endow the agonist with higher activity [7,9,12].Chemokines mediate their effects through interactions with heterotrimeric G-protein-coupled receptors [13][14][15]. Most leukocytes express more than one chemokine receptor and, hence, can respond to more than one chemokine. Additionally, a great variety of in situ experiments demonstrated the concomitant expression of chemokines at target sites of leukocyte trafficking and homing [16][17][18][19][20][21].Many chemokines, apart from being agonistic for their receptors, were shown to act as natural antagonists on one or several receptors in vitro and in vivo [22]. Naturally occurring N-terminal truncations of chemokines have been identified in vivo [23] and numerous enzymes were shown to generate truncations of chemokines that render them less active or inactive [24,25]. Therefore, there are strong indications that a cell needs to 1118integrate more than one signal provided by its environment and that environmental factors other than agonists might influence their responses.Chemokine production can be either constitutive or triggere...

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confidence: 51%

“…Constitutively expressed chemokines act in primary and secondary lymphoid organs [16,17,26] and peripheral tissues [27,28]. The CCR7 ligands, CCL19 and CCL21 [29,30], are expressed in the T-cell area of secondary lymphoid organs as well as on high endothelial venules (HEV) [31] and orchestrate the migration of CCR7 1 cells.…”

mentioning

confidence: 99%

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Kuscher¹,

Danelon²,

Paoletti³

et al. 2009

Eur J Immunol

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“…[26][27][28] One of the best candidates for chemokines is CCL21, which has been proposed to play a role in favoring the interactions between DCs and T cells in secondary lymphoid organs through CCR7 receptor. 4,7,9,29 In fact, mice deficient in the expression of CCL21 showed defects in lymphocyte homing and DC localization, 30 and mice lacking CCR7 receptor also had defects in lymph node architecture. 31 Furthermore, it has been demonstrated that CCL21 could participate itself in lymphoid tissue development and organization in a transgenic model where the CCL21 gene was expressed in pancreatic islets.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5] DCs are professional antigen-presenting cells (APCs) that play a crucial role in initiation of the immune response of both helper and cytotoxic T lymphocytes. 1 DCs reside in many tissues in an immature state with the ability to capture and process antigens, and acquire a mature phenotype with increased cell surface expression of MHC and costimulatory molecules upon uptake of antigen and response to stimuli such as inflammatory cytokines, necrotic cells, and microbial products.…”

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confidence: 99%

Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT

et al. 2004

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To establish a more efficient treatment for immunotherapy against solid tumors, we have evaluated the antitumor effect by coexpression of a chemokine CCL21/secondary lymphoid tissue chemokine and a costimulatory molecule LIGHT in colon carcinoma C26. C26 cells expressing either CCL21 or LIGHT exhibited a significantly reduced tumor growth in vivo, and mice inoculated with these cells showed a prolonged survival, but eventually all these mice died. In contrast, C26 cells expressing both CCL21 and LIGHT exhibited a minimal tumor growth in vivo, and all these mice survived healthily with a tumor remission and consequently acquired a strong protective immunity. A markedly increased infiltration of mature dendritic cells (DCs), and CD8 þ T cells was observed in the tumor mass, and their spleen cells showed a greatly enhanced cytotoxic T lymphocyte (CTL) activity against C26 tumor and interferon (IFN)-g production. Neutralization of IFN-g or depletion of CD8 þ or CD4 þ T cells significantly reduced the antitumor activity. These results suggest that the combined treatment with CCL21 and LIGHT is able to induce a synergistic antitumor effect to eradicate tumor completely by greatly enhancing tumor-infiltration of lymphocytes including mature DCs and CD8 þ T cells, resulting in markedly augmented CTL activity and IFN-g production.

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“…Activation of lymphocytes to induce firm arrest is mediated by tissue-specific chemokines displayed on endothelial surfaces [17]. In mice, HEVs have the ability to produce and display CCL21, the chemokine primarily associated with naïve lymphocyte activation [18,19]. In a truly restricted fashion, CCL21 has the ability to only interact with its specific receptor namely, CCR7, which is uniformly found on naïve and central memory T cells.…”

Section: Process Of Lymphocyte Entry Into Lymph Nodesmentioning

confidence: 99%

Primary immune surveillance: some like it hot

et al. 2007

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The thermal element of fever has been found to be beneficial in models of infectious disease. The contributions of fever-range temperatures to the efficacy of the adaptive immune response have only begun to be delineated. There is accumulating evidence that fever-range thermal stress bolsters primary immune surveillance of lymph nodes and Peyer patches by augmenting lymphocyte extravasation across specialized vessels termed high endothelial venules. Molecular mechanisms have recently come to light by which the thermal component of fever alone may promote lymphocyte trafficking, and thereby the probability of mounting a defense against microbial infection. Acquired knowledge of the molecular changes associated with thermal stress may allow for the development of novel therapies for a variety of disease processes.

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

Cited by 888 publications

References 41 publications

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Synergy‐inducing chemokines enhance CCR2 ligand activities on monocytes

Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT

Primary immune surveillance: some like it hot

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