Correction: Dissecting the Autocrine and Paracrine Roles of the CCR2-CCL2 Axis in Tumor Survival and Angiogenesis.

[This corrects the article DOI: 10.1371/journal.pone.

CCR5 Directs the Mobilization of CD11bGr1Ly6C Polymorphonuclear Myeloid Cells from the Bone Marrow to the Blood to Support Tumor Development.

Cells of hematopoietic origin can be subdivided into cells of the lymphoid lineage and those of the myeloid lineage, among which are myeloid-derived suppressor cells (MDSCs). The MDSCs can be further divided into CD11bLy6GLy6C monocytic (Mo) MDSCs and CD11bLy6GLy6C polymorphonuclear (PMN) MDSCs. Both subtypes support tumor growth and suppress anti-tumor immunity.

CCR5 Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions.

Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using a transgenic mouse melanoma model, we found an accumulation of CCR5 MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression.

CCR8FOXp3 T cells as master drivers of immune regulation.

The current study identifies CCR8 regulatory T cells (T cells) as drivers of immunosuppression. We show that in human peripheral blood cells, more than 30% of T up-regulate CCR8 following activation in the presence of CCL1. This interaction induces STAT3-dependent up-regulation of FOXp3, CD39, IL-10, and granzyme B, resulting in enhanced suppressive activity of these cells.

Mechanism of action and efficacy of RX-111, a thieno[2,3-c]pyridine derivative and small molecule inhibitor of protein interaction with glycosaminoglycans (SMIGs), in delayed-type hypersensitivity, TNBS-induced colitis and experimental autoimmune encephalomyelitis.

Objective And Design: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease.

Materials: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111.

Biased signaling pathways via CXCR3 control the development and function of CD4+ T cell subsets.

Structurally related chemotactic cytokines (chemokines) regulate cell trafficking through interactions with 7-transmembrane domain, G protein-coupled receptors. Biased signaling or functional selectivity is a concept that describes a situation where a 7-transmembrane domain receptor preferentially activates one of several available cellular signaling pathways. It can be divided into 3 distinct cases: ligand bias, receptor bias, and tissue or cell bias.

The Role of Chemokines in Shaping the Balance Between CD4(+) T Cell Subsets and Its Therapeutic Implications in Autoimmune and Cancer Diseases.

Chemokines are the key activators of adhesion molecule and also drivers of leukocyte migration to inflammatory sites and are therefore mostly considered as proinflammatory mediators. Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity. Along with this, a single chemokine named CXCL10 could be used to induce antitumor immunity, and thereby suppress myeloma.

Duodenal Expression of 25 Hydroxyvitamin D3-1α-hydroxylase Is Higher in Adolescents Than in Children and Adults.

Context: Puberty is associated with increased dietary calcium absorption. However, little is known about the metabolic adaptations that enhance calcium absorption during puberty.

Objectives: To investigate duodenal 25-hydroxy vitamin D-1α-hydroxylase (CYP 27B1) mRNA expression and duodenal 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) production in children, adolescents, and adults.

The role of chemokines in adjusting the balance between CD4+ effector T cell subsets and FOXp3-negative regulatory T cells.

Chemokines are small (~8-14 kDa) structurally-related chemotactic cytokines that regulate cell trafficking through interactions with specific seven-trans membrane, G protein-coupled receptors (GPCRs). One of the important features of G protein-coupled receptors (GPCRs) is their ability to transmit diverse signaling cascades upon binding different ligands. The current review focuses on the interplay between three ligands: CXCL9, CXCL10 and CXCL11 binding the same receptor (CXCR3) on CD4+ T cells, yet direct different signaling cascades to shape T cell mediated immunity.

CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis.

A single G protein-coupled receptor (GPCR) can activate multiple signaling cascades based on the binding of different ligands. The biological relevance of this feature in immune regulation has not been evaluated. The chemokine-binding GPCR CXCR3 is preferentially expressed on CD4+ T cells, and canonically binds 3 structurally related chemokines: CXCL9, CXCL10, and CXCL11.

The role of vitamin D receptor in innate and adaptive immunity: a study in hereditary vitamin D-resistant rickets patients.

Context: Vitamin D has regulatory effects on innate and adaptive immunity. Curiously, hereditary vitamin D-resistant rickets (HVDRR) patients show no increased incidence of infectious or autoimmune diseases.

Objectives: The aim of the study was to investigate the role of vitamin D and the vitamin D receptor (VDR) in innate and adaptive immune responses in monocytes and lymphocytes from HVDRR patients.

Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis.

The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX₃CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2-/-, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX₃CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX₃CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx₃cr1(gfp)), together with the CD45.

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ.

A fusion protein encoding the second extracellular domain of CCR5 arrests chemokine-induced cosignaling and effectively suppresses ongoing experimental autoimmune encephalomyelitis.

CCR5 is a key CCR that is highly expressed on CD4(+) T cells. It binds three different ligands: CCL3 (MIP-alpha), CCL4 (MIP-beta), and CCL5 (RANTES). Recent studies suggested that the interaction between CCR5 and its ligands is essential not only for attracting these CCR5(+) T cells but also substantial for transuding cosignals for their activation.

Antigen-specific CD25- Foxp3- IFN-gamma(high) CD4+ T cells restrain the development of experimental allergic encephalomyelitis by suppressing Th17.

The current study identifies within the Th1 subtype two distinct CD4(+) populations: those capable of transferring inflammatory autoimmunity and others that regulate its development by suppressing Th17 in an interferon (IFN)-gamma-dependent manner. These CD4(+)IFN-gamma(high)IL-4(low)IL-10(low)TGF-beta(low)FOXp3(-) cells in fact function as antigen-specific regulatory cells that restrain the development of autoimmunity by increasing the threshold of Th17 activation. We show that development of autoimmune conditions within the central nervous system is dependent on the Fas ligand-mediated apoptosis of these regulatory cells at early stages of disease.

Predominant expression of CCL2 at the tumor site of prostate cancer patients directs a selective loss of immunological tolerance to CCL2 that could be amplified in a beneficial manner.

We have previously shown that, during inflammatory autoimmune diseases in humans, the immune system develops a neutralizing auto-Ab-based response to a very limited number of inflammatory mediators, and that amplification of each response could be beneficial for the host. Our working hypothesis has been that this selective breakdown of immunological tolerance is due to a predominant expression of an inflammatory mediator at an immune-restricted site undergoing a destructive process. All three conditions also take place in cancer diseases.

A novel recombinant fusion protein encoding a 20-amino acid residue of the third extracellular (E3) domain of CCR2 neutralizes the biological activity of CCL2.

CCL2 is a key CC chemokine that has been implicated in a variety of inflammatory autoimmune diseases and in tumor progression and it is therefore an important target for therapeutic intervention in these diseases. Soluble receptor-based therapy is a known approach for neutralizing the in vivo functions of soluble mediators. Owing to the complexity of seven-transmembrane G protein-coupled receptors, efforts to generate neutralizing soluble chemokine receptors have so far failed.

Selective autoantibody production against CCL3 is associated with human type 1 diabetes mellitus and serves as a novel biomarker for its diagnosis.

We have recently demonstrated that patients suffering from chronic autoimmune diseases develop an autoantibody response against key mediators that participate in the initiation and progression of these diseases. In this paper, we show that patients with type 1 diabetes mellitus (T1DM), but not those suffering from several other inflammatory autoimmune diseases, display a selective autoantibody titer to a single CC chemokine named CCL3. From the diagnostic point we show that this response could be used as a biomarker for diagnosis of T1DM, a disease that is currently diagnosed by autoantibodies to competitive anti-insulin Abs, islet cell Abs, and glutamic acid decarboxylase Abs.

CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells.

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell-derived factor 1alpha), redirects the polarization of effector Th1 cells into CD4(+)CD25(-)Foxp3(-)interleukin (IL) 10(high) antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10-deficient mice.

Coadministration of plasmid DNA constructs encoding an encephalitogenic determinant and IL-10 elicits regulatory T cell-mediated protective immunity in the central nervous system.

We have previously shown that Ag-specific IL-10-producing regulatory T cells (Tr1) participate in the regulation of experimental autoimmune encephalomyelitis and that their specificity undergoes determinant spread in a reciprocal manner to effector T cell specificity. The current study shows that coadministration of plasmid DNA vaccines encoding IL-10 together with a plasmid encoding a myelin basic protein (MBP) encephalitogenic determinant during an ongoing disease rapidly amplifies this Tr1-mediated response, in a disease-specific manner. Thus, coadministration of both plasmids, but not the plasmid DNA encoding MBP alone, rapidly suppresses an ongoing disease.