Pattern Of Chemokine Receptors Research Articles

Dynamic Dimerization of Chemokine Receptors and Potential Inhibitory Role of Their Truncated Isoforms Revealed through Combinatorial Prediction.

Chemokine receptors play crucial roles in fundamental biological processes. Their malfunction may result in many diseases, including cancer, autoimmune diseases, and HIV. The oligomerization of chemokine receptors holds significant functional implications that directly affect their signaling patterns and pharmacological responses. However, the oligomerization patterns of many chemokine receptors remain poorly understood. Furthermore, several chemokine receptors have highly truncated isoforms whose functional role is not yet clear. Here, we computationally show homo- and heterodimerization patterns of four human chemokine receptors, namely CXCR2, CXCR7, CCR2, and CCR7, along with their interaction patterns with their respective truncated isoforms. By combining the neural network-based AlphaFold2 and physics-based protein-protein docking tool ClusPro, we predicted 15 groups of complex structures and assessed the binding affinities in the context of atomistic molecular dynamics simulations. Our results are in agreement with previous experimental observations and support the dynamic and diverse nature of chemokine receptor dimerization, suggesting possible patterns of higher-order oligomerization. Additionally, we uncover the strong potential of truncated isoforms to block homo- and heterodimerization of chemokine receptors, also in a dynamic manner. Our study provides insights into the dimerization patterns of chemokine receptors and the functional significance of their truncated isoforms.

"Evaluation of the Effect of α-L-Guluronic Acid (G2013), as a New Member of NSAID Family, on Expression Pattern of Chemokine Receptors in Systemic Lupus Erythematosus"

"Evaluation of the Effect of α-L-Guluronic Acid (G2013), as a New Member of NSAID Family, on Expression Pattern of Chemokine Receptors in Systemic Lupus Erythematosus"

Effect of Clonally Expanded PD-1high CXCR5-CD4+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis.

Antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA. Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1high CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next-generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro. Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)-coexpressing PD-1high CXCR5-HLA-DR+CD4+ T cells that accumulate in the joints of ANA-positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T-bet and B lymphocyte-induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL-21 and IFNy, skewed B cell differentiation toward a CD21low/- CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21low/- CD11c+CD27-IgM- double-negative (DN) B cells in situ. Clonally expanded CD4+ Tph cells accumulate in the joints of ANA-positive JIA patients and, in particular, promote CD21low/- CD11c+ DN B cell differentiation. The expansion of Tph cells and DN B cells might reflect the autoimmune response in the joints of ANA-positive JIA patients.

Monocyte-Derived Dendritic Cell Differentiation in Inflammatory Arthritis Is Regulated by the JAK/STAT Axis via NADPH Oxidase Regulation.

Monocyte-derived Dendritic cells (Mo-DC) are a distinct DC subset, involved in inflammation and infection, they originate from monocytes upon stimulation in the circulation and their activation and function may vary in autoimmune diseases. In this study we investigate the differences in Mo-DC differentiation and function in patients with Rheumatoid (RA) compared to Psoriatic arthritis (PsA). A significant increase in the Mo-DC differentiation marker CD209, paralleled by a corresponding decrease in the monocytic marker CD14, was demonstrated in RA compared to PsA, as early as 1 day post Mo-DC differentiation. RA monocytes ex-vivo were phenotypically different to PsA, displaying a more mature phenotype associated with altered cellular-morphology, early dendrite formation, and a significant increase in the CD40 marker. In addition, SPICE algorithm flow cytometric analysis showed distinct differences in chemokine receptors distribution in HC compared to PsA and RA CD14+ cells in the blood, with increased expression of the chemokine receptors CCR7 and CXCR4 observed in PsA and RA. In addition CD14+ cells at the site of inflammation showed a different chemokine receptor pattern between PsA and RA patients, with higher expression of CXCR3 and CXCR5 in RA when compared to PsA. The early priming observed in RA resulted in monocyte-endocytosis and antigen-uptake mechanisms to be impaired, effects that were not observed in PsA where phagocytosis capacity remained highly functional. Tofacitinib inhibited early Mo-DC differentiation, decreasing both CD209 and CD40 activation markers in RA. Inhibition of Mo-DC differentiation in response to Tofacitinib was mediated via an imbalance in the activation of NADPH-oxidases NOX5 and NOX2. This effect was reversed by NOX5 inhibition, but not NOX2, resulting in suppression of NOX5-dependent ROS production. In conclusion, RA monocytes are already primed ex vivo to become DC, evident by increased expression of activation markers, morphological appearance and impaired endocytosis capacity. Furthermore, we demonstrated for the first time that NOX5 mediates Mo-DC differentiation and function in response to Tofacitinib, which may alter DC functions.

The Complexity of Targeting Chemokines to Promote a Tumor Immune Response.

Immunotherapeutic treatment strategies greatly extend patient survival following malignant disease across a wide range of tumor types, including even those with metastatic disease. While diverse in approach, adoptive cell therapy, introduction of T cells that express chimeric antigen receptors, and checkpoint inhibitors all aim to re-invigorate the immune system to promote tumor cell identification and elimination. This review will focus on immune cell infiltration into tumors as well as a cellular organization within the tumor microenvironment as directed by the cell-specific expression patterns of chemokines and chemokine receptors. Through better understanding the chemokine network within tumors, we can uncover mechanisms to promote beneficial immune cell infiltration that can be combined with checkpoint inhibition. Conversely, chemokine expression is not limited to cells of the immune system, and it is understood that tumor cells also express chemokines and chemokine receptors. Tumor cells can hijack the chemokine networks to promote immune suppression and metastatic tumor cell trafficking. We will discuss the ways in which the chemokine network lies at the crossroad of immune evasion and tumor regression. Overall, this review will summarize key publications in the field of immune cell recruitment to tumors, highlight the dichotomous nature of chemokine interventions into cancer, and aims to identify therapeutic pathways forward.

Comprehensive immune profiling of patients (pts) with metastatic urothelial cancer (mUC) or renal cell cancer (mRCC) receiving immune checkpoint inhibitors (CPIs).

532 Background: CPIs have had a major impact on pts with mUC and mRCC. Only a small subset of pts benefit from CPI, and predictive biomarkers are needed. The role of circulating immune cells is poorly understood, but early changes after CPI exposure may predict response. We aimed to study the changes in circulating immune cell populations of pts receiving CPIs. Methods: Whole blood was collected prior to, and 3 wks after initiation of CPI in CPI-naïve pts with mUC or mRCC. PBMCs were isolated and profiled using mass cytometry (CyTOF) to provide a comprehensive overview of immune cell populations, expression of immune checkpoints, proliferation, and viability. Expression of chemokine receptors and cytokines was measured by flow cytometry. Treatment-emergent changes were correlated with response. Effects of treatment were determined by Wilcoxon signed-rank test; interactions of treatment and other variables like cluster size were determined by repeated measures two-way ANOVA. Any effects described had a significance of p<0.05. Results: Ten pts enrolled in this pilot study (mRCC = 4, mUC = 6) received anti-PDL1 (n=5), anti-PDL1/anti-CTLA4 (n=3), and anti-PDL1/chemotherapy (n=2). Best response was: 1 CR, 3 PR, 2 SD, 4 PD. Treatment induced an increase in dendritic cells (DC) and a decrease in PD1+ CD4+ and CD8+ T-cells. Elevated Ki-67, CTLA-4, LAMP-1, granzyme B and perforin expression in PD1+ cells post CPI suggested re-invigoration of exhausted T-cells. PD1+ T-cells had increased expression of the chemokine receptors CCR4 and CCR5, and decreased expression of CCR7 and CXCR4, irrespective of treatment. Response was associated with fewer CCR4+ CD4+ T cells and fewer PD1+ CD8+ T cells. Conclusions: Deep profiling by CyTOF provides a means of immune monitoring, with potential applications in clinical trials involving CPIs. Immune responses to CPIs are heterogeneous, with pt subgroups segregated by shifts in both T cell and DCs, and patterns of chemokine receptors and cytokines. Therapy reinvigorates exhausted T cells, and may cause these cells to infiltrate tumors or tumor-draining lymph nodes via chemokine receptors.

Foliate Lymphoid Aggregates as Novel Forms of Serous Lymphocyte Entry Sites of Peritoneal B Cells and High-Grade B Cell Lymphomas.

The cellular homeostasis of lymphoid tissues is determined by the continuous interactions of mobile hematopoietic cells within specialized microenvironments created by sessile stromal cells. In contrast to the lymph nodes and mucosal lymphoid tissues with well-defined entry and exit routes, the movement of leukocytes in the peritoneal cavity is largely unknown. In this study, we report that, in addition to the omental milky spots and fat-associated lymphoid clusters, in mice, the serous surface of the mesenteric adipose streaks contains lymphocyte-rich organoids comprised of a highly compacted leaf-like part connected to the adipose tissue that can also efficiently bind B cells and high-grade B cell lymphoma (diffuse large B cell lymphoma) cells. Denoted as foliate lymphoid aggregates (FLAgs), these structures show incomplete T/B segregation and a partially differentiated stromal architecture. LYVE-1-positive macrophages covering FLAgs efficiently bind i.p. injected normal B cells as well as different types of diffuse large B cell lymphoma cells. Within FLAgs, the lymphocytes compartmentalize according to their chemokine receptor pattern and subsequently migrate toward the mesenteric lymph nodes via the mesenteric lymphatic capillaries. The blood supply of FLAgs includes short vascular segments displaying peripheral lymph node addressin, and the extravasation of lymphocytes to the omental and mesenteric adipose tissues is partly mediated by L-selectin. The appearance of i.p. injected cells in mesenteric lymph nodes suggests that the mesentery-associated lymphatics may also collect leukocytes from the fat-associated lymphoid clusters and FLAgs, thus combining the mucosal and serous exit of mobile leukocytes and increasing the range of drainage sites for the peritoneal expansion of lymphoid malignancies.

E-protein-regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex.

Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR-CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4-CXCL12 engagements release preselection thymocytes from the thymic cortex. We further document that CXCR4 expression must be extinguished by TCR-mediated positive selection signals to allow migration of TCR-signaled thymocytes out of the thymic cortex into the medulla. Thus, E-protein transcription factors regulate the ordered expression pattern of chemokine receptors on developing thymocytes, and the interaction of the chemokine receptor CXCR4 with its ligand adheres TCR-unsignaled preselection thymocytes to the thymic cortex.

Chemokine receptor expression on peripheral blood T-helper cells in Helicobacter pylori-associated diseases: chronic gastroduodenitis and peptic ulcer disease

Helicobacter pylori represents a pathogen causing chronic infection in around a half of the global human population, which manifestations vary from asymptomatic infection to developing gastritis and peptic ulcer. The data accumulated suggest that overt clinical types of this infection are associated with lost immunoregulation and increased pro-inflammatory cell-mediated immune response triggered by H. pylori-specific T helper cells. Here, we examined the degree of peripheral blood CD4+ T cell maturity and related expression of chemokine receptors involved in migration to gastrointestinal tract (CCR9 and CCR6), as well as Тand B-cell zones of lymphoid organs (CCR7 and CXCR5). It was shown that overt H. pylori-infection was coupled to changes in expression pattern of chemokine receptors on T helper cells. In particular, percentage of mature CD4+CD45RO+ T cells bearing CCR9 and immature CD4+CD45RO– Т cells expressing CXCR5 was increased in peripheral blood of patients with chronic gastroduodenitis. However, increased amount of activated mature CD4+CD45RO+ICOS+ T cells was observed in patients with chronic gastroduodenitis comorbid with peptic ulcer that was also associated with elevated amount of mature CCR6+ T helpers (mainly CD4+CD45RO+CCR7– CCR6+ cells) and follicular T helper cells as well as emerging minor CD4+CD45RO+CXCR5+CCR6+.T cell subset, not affecting CD4+CCR9+ Т cells. Thus, the data obtained evidence that tissue-specific T-helper cell migration is controlled separately in of H. pylori-associated diseases.

Long-Term Engraftment of ESC-Derived B-1 Progenitor Cells Supports HSC-Independent Lymphopoiesis.

SummaryIt is generally considered that mouse embryonic stem cell (ESC) differentiation into blood cells in vitro recapitulates yolk sac (YS) hematopoiesis. As such, similar to YS-derived B-progenitors, we demonstrate here that ESC-derived B-progenitors differentiate into B-1 and marginal zone B cells, but not B-2 cells in immunodeficient mice after transplantation. ESC-derived B-1 cells were maintained in the recipients for more than 6 months, secreting natural IgM antibodies in vivo. Gene expression profiling displayed a close relationship between ESC- and YS-derived B-1 progenitors. Because there are no hematopoietic stem cells (HSCs) detectable in our ESC differentiation culture, successful long-term engraftment of ESC-derived functional B-1 cells supports the presence of HSC-independent B-1 cell development.

The immune microenvironment in malignant lymphoma

Recent advances in immunotherapy have highlighted the importance of the tumor microenvironment. Lymphomas are a heterogeneous group of malignancies that arise from lymphocytes and typically develop in lymphoid tissues. It has been recognized that the elements of the lymphoma microenvironment are not mere bystanders to a host antitumor inflammatory response but are important components of the tumor that support proliferation, survival, and chemoresistance of lymphoma cells. Lymphoma cells have individual expression patterns of chemokine receptors and adhesion molecules, according to their histological subtypes, and the patterns of surface molecules determine the sites of tumor involvement. Lymphoma cells often depend on the signals provided by non-tumor cells, such as stromal cells and macrophages, through direct cell contact and paracrine factors. On the other hand, there are genetic and non-genetic mechanisms allowing lymphoma cells to escape from anti-tumor immunity, such as downregulation of HLA molecules, B2M, CD58, CD70, and/or upregulation of PD-L1 and PD-L2. Further understanding of the interactions of lymphoma cells and the tumor microenvironment gives an insight into the pathogenesis of lymphomas and supports new approaches to their treatment.

Hypoxia Modifies the Transcriptome of Human NK Cells, Modulates Their Immunoregulatory Profile, and Influences NK Cell Subset Migration.

Hypoxia, which characterizes most tumor tissues, can alter the function of different immune cell types, favoring tumor escape mechanisms. In this study, we show that hypoxia profoundly acts on NK cells by influencing their transcriptome, affecting their immunoregulatory functions, and changing the chemotactic responses of different NK cell subsets. Exposure of human peripheral blood NK cells to hypoxia for 16 or 96 h caused significant changes in the expression of 729 or 1,100 genes, respectively. Gene Set Enrichment Analysis demonstrated that these changes followed a consensus hypoxia transcriptional profile. As assessed by Gene Ontology annotation, hypoxia-targeted genes were implicated in several biological processes: metabolism, cell cycle, differentiation, apoptosis, cell stress, and cytoskeleton organization. The hypoxic transcriptome also showed changes in genes with immunological relevance including those coding for proinflammatory cytokines, chemokines, and chemokine-receptors. Quantitative RT-PCR analysis confirmed the modulation of several immune-related genes, prompting further immunophenotypic and functional studies. Multiplex ELISA demonstrated that hypoxia could variably reduce NK cell ability to release IFNγ, TNFα, GM-CSF, CCL3, and CCL5 following PMA+Ionomycin or IL15+IL18 stimulation, while it poorly affected the response to IL12+IL18. Cytofluorimetric analysis showed that hypoxia could influence NK chemokine receptor pattern by sustaining the expression of CCR7 and CXCR4. Remarkably, this effect occurred selectively (CCR7) or preferentially (CXCR4) on CD56bright NK cells, which indeed showed higher chemotaxis to CCL19, CCL21, or CXCL12. Collectively, our data suggest that the hypoxic environment may profoundly influence the nature of the NK cell infiltrate and its effects on immune-mediated responses within tumor tissues.

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.

Chemokine receptor co-expression reveals aberrantly distributed TH effector memory cells in GPA patients

BackgroundPersistent expansion of circulating CD4+ effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4+ TEM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4+ TEM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4+ TEM cells subsets may reveal distinct contributions of specific CD4+ TEM subsets to the disease pathogenesis in GPA.MethodPeripheral blood of 63 GPA patients in remission and 42 age- and sex-matched healthy controls was stained immediately after blood withdrawal with fluorochrome-conjugated antibodies for cell surface markers (CD3, CD4, CD45RO) and chemokine receptors (CCR4, CCR6, CCR7, CRTh2, CXCR3) followed by flow cytometry analysis. CD4+ TEM memory cells (CD3+CD4+CD45RO+CCR7-) were gated, and the expression patterns of chemokine receptors CXCR3+CCR4-CCR6-CRTh2-, CXCR3-CCR4+CCR6-CRTh2+, CXCR3-CCR4+CCR6+CRTh2-, and CXCR3+CCR4-CCR6+CRTh2- were used to distinguish TEM1, TEM2, TEM17, and TEM17.1 cells, respectively.ResultsThe percentage of CD4+ TEM cells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4+ TEM cell population demonstrated a significant increase in the proportion of TEM17 cells with a concomitant significant decrease in the TEM1 cells in GPA patients compared to HC. The percentage of TEM17 cells correlated negatively with TEM1 cells in GPA patients. Moreover, the circulating proportion of TEM17 cells showed a positive correlation with the number of organs involved and an association with the tendency to relapse in GPA patients. Interestingly, the aberrant distribution of TEM1 and TEM17 cells is modulated in CMV- seropositive GPA patients.ConclusionsOur data demonstrates the identification of different CD4+ TEM cell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between TEM1 and TEM17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.

Chemokine and chemokine receptor patterns in patients with benign and malignant salivary gland tumors: a distinct role for CCR7.

To explore the molecular mechanisms involved in pathophysiology of malignant and benign salivary gland tumors (SGTs), we investigated main tumor-inducing chemokines and chemokine receptors, CXCL12/CXCR4/ACKR3 (CXCR7), CXCR3/CXCL10, CCR5/CCL5, CCL21/CCR7, CCL2, CCR4, CXCR5, CCR6, and CXCL8 in tumor tissues. Parotid tissues were obtained from 30 patients with malignant and benign SGTs. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the mRNA expression pattern of the mentioned chemokines/chemokine receptors and immunohistochemistry (IHC) was performed to verify the expression of CCR7. Expression levels of CCR7 and CCR4 transcripts were higher in the tumor tissues of malignant cases in comparison to benign ones (p=0.03 and 0.02). Immunohistochemistry analysis confirmed that the protein level of CCR7 concurred with the mRNA expression. CCL2 gene transcripts were observed with a higher expression in patients with tumor-free lymph nodes (LN-) and early stages, whereas CCR7 transcript was higher in LN+ and late stages of the disease. A significant inverse correlation was found between CXCL10 transcript and tumor size in benign cases. The mRNA expression of CCR7, CCR4, CXCR3, CCL21, CCL5, and CXCL12 was significantly higher in mucoepidermoid carcinoma in comparison to pleomorphic adenoma subtypes (p<0.05). On the basis of the present study, it was determined that malignant and benign SGTs exhibit a distinct pattern of chemokines and chemokine receptors, which are probably associated with known biological and clinical behaviors of these tumors. Significant increased CCR4 and CCR7 expression in malignant SGTs might play a central role in malignant transformation that introduces them as new targets for cancer immunotherapy.

Chemokine receptor patterns and right heart failure in mechanical circulatory support

Right ventricular failure (RVF) complicates 9% to 44% of left ventricular assist device (LVAD) implants post-operatively. Current prediction scores perform only modestly in validation studies, and do not include immune markers. Chemokines are inflammatory signaling molecules with a fundamental role in cardiac physiology and stress adaptation. In this study we investigated chemokine receptor regulation in LVAD recipients who develop RVF. Expression of chemokine receptor (CCR) genes 3 to 8 were examined in the peripheral blood of 111 LVAD patients, collected 24 hours before implant. RNA was isolated using a PAXgene protocol. Gene expression was assessed using a targeted microarray (RT2 Profiler PCR Array; Qiagen). Results were expressed as polymerase chain reaction (PCR) cycles to threshold and normalized to the average of 3 control genes, glyceraldehyde phosphate dehydrogenase (GAPDH), hypoxanthine phosphoribosyltransferase 1 (HPRT1) and β2-microglobulin (B2M). Secondary outcomes studied were 1-year mortality and long-term RV failure (RVF-LT). CCR3, CCR4, CCR6, CCR7 and CCR8 were downregulated in LVAD recipients with RVF. Within this cohort of patients, CCR4, CCR7 and CCR8 were further downregulated in those who required RV mechanical support. In addition, under-expression of CCR3 to CCR8 was independently associated with an increased risk of mortality at 1 year, even after adjusting for RVF. CCR expression did not predict RVF-LT in our patient cohort. Pre-LVAD CCR downregulation is associated with RVF and increased mortality after implant. Inflammatory signatures may play a major role in prognostication in this patient population.

Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma.

Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.

Abnormal expression of chemokine receptor on B cells in patients with SLE

SLE is a systemic autoimmune disease characterized by overactivation of autoreactive memory B cells. However, little is known about the mechanism of qualitative abnormality of B cells. The subset classification of T cells by expression pattern of master transcription factors and chemokine receptors has been established. The biology of T cells is useful information to assess qualitative abnormality of B cells. Therefore, we focused on the expression of chemokine receptors such as CXCR5 and CXCR3 on B cells in order to define the B cell subset classification in patients with SLE. Our results revealed that pathological B cells, which lose CXCR5 and express CXCR3, might be involved in autoantibody production through the interaction with Tfh cells, and in acquisition of effector function of memory B cells during the pathological process in SLE. In addition, the results revealed that those effector B cells still remained after improvement of disease activity by immunosuppressive therapy, indicating that the quantitative abnormality, which is not improved by current therapy, may underlie in this disease.

Chemokines and skin diseases.

Chemokines are small molecules that induce chemotaxis and activation of certain subsets of leukocytes. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. CCL17 expressed by Langerhans cells, blood endothelial cells, and fibroblasts plays a key role in attracting Th2 cells and tumor cells of adult T-cell leukemia/lymphoma and mycosis fungoides/Sézary syndrome into the skin, developing various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3-expressing cells such as Th2 cells and eosinophils. CCL11 may also serve as an autocrine as well as a paracrine in anaplastic large cell lymphoma. CX3CL1 expressed on blood endothelial cells leads to infiltration of CX3CR1(+) immune cells, such as mast cells, neutrophils, and macrophages, playing important roles in wound healing, tumor immunity, and vasculitis. Biologics targeting chemokines and their receptors are promising strategies for various skin diseases that are resistant to the current therapy.

Interleukins 15 and 12 in combination expand the selective loss of natural killer T cells in HIV infection in vitro.

The present study evaluated the frequency and receptor expression pattern of invariant natural killer T (iNKT) cells in human immunodeficiency virus (HIV)-infected individuals. Further, the effect of IL-15 + IL-12 stimulation on iNKT cells was also assessed. The study included 15 individuals each from normal healthy subjects, pulmonary tuberculosis patients, HIV-infected individuals, and patients with HIV and tuberculosis coinfection (HIV-TB). The frequency of iNKT cells and the expression of phenotype, cytotoxic and chemokine receptors were studied by flow cytometry. The number of iNKT cells was significantly depleted in HIV and HIV-TB patients, which upon IL-15 + IL-12 stimulation expanded in HIV. The constitutively expressed natural cytotoxicity receptor, NKp46 was increased in HIV and HIV-TB, which might be the host's response to HIV replication. The distinct expression patterns of chemokine and adhesion receptors suggest that iNKT subsets might traffic to different microenvironment and tissues. High expression of chemokine receptor CCR5 by most iNKT cells suggests that these cells might be more favorable targets of HIV infection. Our results show that IL-15 and IL-12 combination has the ability to expand the selective depletion of iNKT cells in vitro in HIV-infected individuals, but of limited value when coinfected with TB.