Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity.

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

CC and CXC chemokines play key roles in the development of polyomaviruses related pathological conditions.

It has been reported that polyomaviruses are the microbes which can be a cause of several human pathological conditions including cancers, nephropathy, progressive multifocal leukoencephalopathy and gynaecological disease. Although investigators proposed some mechanisms used by the viruses to induce the disorders, the roles played by chemokines in the pathogenesis of polyomaviruses infections are yet to be clarified. This review article investigated recent studies regarding the roles played by chemokines in the pathogenesis of the polyomaviruses infections. The research in the literature revealed that CXC chemokines, including CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CXCL16, significantly participate in the pathogenesis of polyomaviruses. CC chemokines, such as CCL2, CCL5 and CCL20 also participate in the induction of the pathological conditions. Therefore, it appears that CXC chemokines may be considered as the strategic factors involved in the pathogenesis of polyomaviruses.

The ERß-CXCL19/CXCR4-NFκB pathway is critical in mediating the E2-induced inflammation response in the orange-spotted grouper (Epinephelus coioides).

The main physiological function of 17ß-estradiol (E2) in vertebrates is to regulate sexual development and reproduction. In fish, especially hermaphroditic fish, estrogen is often used to aid reproduction, but it also can trigger an inflammatory response. However, the molecular mechanism for this E2-induced inflammatory reaction is not clear. In this study, we found that the ERß-CXCL19/CXCR4-NFκB cascade regulated the E2-induced inflammatory response in the orange-spotted grouper (Epinephelus coioides). Strikingly, E2 treatment resulted in significantly high expression of inflammatory cytokines and induced phosphorylation and degradation of IκBα and translocation of NFκB subunit p65 to the nucleus in grouper spleen cells. However, the E2-induced inflammatory response could be prevented by the broad estrogen receptor (ER) ligand ICI 182,780. Moreover, the luciferase assay showed that E2 induced the inflammatory response by activating the promotor of chemokine CXCL19 through ERß1 and ERß2. Knockdown of CXCL19 blocked the E2-induced inflammatory response and NFκB nucleus translocation. Additionally, knockdown of chemokines CXCR4a and CXCR4b together, but not alone, blocked the E2-induced inflammatory response. The immunofluorescence assay and co-immunoprecipitation analysis showed that CXCL19 mediated the E2-induced inflammatory response by activating CXCR4a or CXCR4b. Taken together, these results showed that the ERß-CXCL19/CXCR4-NFκB pathway mediated the E2-induced inflammatory response in grouper. These findings are valuable for future comparative immunological studies and provide a theoretical basis for mitigating the adverse reactions that occur when using E2 to help fish reproduce.

Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer.

Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.

Identification of tissue-specific expression of CXCL14 in black rockfish (Sebastes schlegelii).

CXCL14 is a chemokine which is orthologous in mammals and fish. CXCL14 has a functional role in different organs, with immunomodulatory functions in mammals, but its expression and function in fish is not well known. Moreover, it shows no effects related to immunity in the central nervous system or the reproductive tract in diverse species. Black rockfish (Sebastes schlegelii) is an economically important fish in Asian countries, whose CXCL14 expression pattern is yet to be understood. In this study, the homology of the CXCL14 amino acid sequence in S. schlegelii was compared with that in other species, including fish. Moreover, in situ hybridization analysis revealed that it was highly expressed in the brain and ovary of S. schlegelii. Taken together, we identified for the first time, the cell-specific expression of CXCL14 in S. schlegelii.

CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.

The C-X-C motif chemokine ligand 17 (CXCL17) is chemotactic for myeloid cells, exhibits bactericidal activity, and exerts anti-viral functions. This chemokine is constitutively expressed in the respiratory tract, suggesting a role in lung defenses. However, little is known about the participation of CXCL17 against relevant respiratory pathogens in humans. Here, we evaluated the serum levels and lung tissue expression pattern of CXCL17 in a cohort of patients with severe pandemic influenza A(H1N1) from Mexico City. Peripheral blood samples obtained on admission and seven days after hospitalization were processed for determinations of serum CXCL17 levels by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 was assessed by immunohistochemistry (IHQ) in lung autopsy specimens from patients that succumbed to the disease. Serum CXCL17 levels were also analyzed in two additional comparative cohorts of coronavirus disease 2019 (COVID-19) and pulmonary tuberculosis (TB) patients. Additionally, the expression of CXCL17 was tested in lung autopsy specimens from COVID-19 patients. A total of 122 patients were enrolled in the study, from which 68 had pandemic influenza A(H1N1), 24 had COVID-19, and 30 with PTB. CXCL17 was detected in post-mortem lung specimens from patients that died of pandemic influenza A(H1N1) and COVID-19. Interestingly, serum levels of CXCL17 were increased only in patients with pandemic influenza A(H1N1), but not COVID-19 and PTB. CXCL17 not only differentiated pandemic influenza A(H1N1) from other respiratory infections but showed prognostic value for influenza-associated mortality and renal failure in machine-learning algorithms and regression analyses. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages increase their CXCL17 production capacity after influenza A(H1N1) pdm09 virus infection. Our results for the first time demonstrate an induction of CXCL17 specifically during pandemic influenza A(H1N1), but not COVID-19 and PTB in humans. These findings could be of great utility to differentiate influenza and COVID-19 and to predict poor prognosis specially at settings of high incidence of pandemic A(H1N1). Future studies on the role of CXCL17 not only in severe pandemic influenza, but also in seasonal influenza, COVID-19, and PTB are required to validate our results.

Mucosal chemokine CXCL17: What is known and not known.

CXCL17, the last described chemokine, has recently been found to be abundantly and specifically expressed in mucosal sites, while its receptor is still not well determined. Accumulative studies indicate that CXCL17 could potentially exhibit chemotactic, anti-inflammatory, antimicrobial activities under multiple biological conditions. However, the mechanism by which it contributes to the physiological and pathological processes within specific mucosal tissues is still far from being fully elucidated. In this present review, we therefore summarize the current available evidence of CXCL17 with specific emphasis on its biological role and pathophysiological significance, in order to aid in the advancement of CXCL17-related studies.

The evolution and functional characterization of CXC chemokines and receptors in lamprey.

Chemokines are a large family of soluble peptides guiding cell migration in development and immune defense. They interact with chemokine receptors and are essential for the coordination of cell migration in diverse physiological processes. The CXC subfamily is one of the largest groups in the chemokine family and consists of multiple members. In this study, we identified homologues of three chemokine ligands (CXCL8, CXCL_F5 and CXCL12) and two CXC receptor like molecules (CXCR_L1 and CXCR_L2) in lamprey. Sequence analysis revealed that they share the same genomic organization with their counterparts in jawed vertebrates but synteny was not conserved. Lamprey CXCL8 and CXCL12 have four conserved cysteine residues whilst the CXCL_F5 has two additional cysteine residues. In addition, CXCL_F5 is evolutionarily related to the fish specific CXC chemokine groups previously identified and contains multiple cationic aa residues in the extended C- terminal region. The two CXCRs possess seven transmembrane domains and conserved structural elements for receptor activation and signaling, including the DRYXXI(V)Y motif in TM2, the disulphide bond connecting ECL2 and TM3, the WXP motif in TM6 and NPXXY motif in TM7. The identified CXC chemokines and receptors were constitutively expressed in tissues including the liver, kidney, intestine, heart, gills, supraneural body and primary leukocytes, but exhibited distinct expression patterns. Relatively high expression was detected in the gills for CXCL8, CXCL_F5 and CXCR_L1 and in the supraneural body for CXCL12 and CXCR_L2. All the genes except CXCL12 were upregulated by stimulation with LPS, pokeweed and bacterial infection, and the CXCL8 and CXCL_F5 was induced by poly (I:C). Functional analysis showed that the CXCL8 and CXCL_F5 specifically interacted with CXCR_L1 and CXCR_L2, respectively. Our results demonstrate that the CXC chemokine system had diversified in jawless fish.

A Critical Role for the CXCL3/CXCL5/CXCR2 Neutrophilic Chemotactic Axis in the Regulation of Type 2 Responses in a Model of Rhinoviral-Induced Asthma Exacerbation.

Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model of RV-induced exacerbation of asthma attenuated the accumulation of CXCR2+ neutrophils, eosinophils, and innate lymphoid cells in the lung and decreased production of type 2 regulatory factors IL-25, IL-33, IL-5, IL-13, CCL11, and CCL24. Suppression of inflammation was associated with decreased airways hyperreactivity, mucus hypersecretion, and collagen deposition. Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma.

The cytomegalovirus UL146 gene product vCXCL1 promotes the resistance of hepatic cells to CD8+ T cells through up-regulation of PD-L1.

The HCMV (human cytomegalovirus) encodes numerous proteins which function to evade the immune response, which allows the virus to replicate. Exploring the mechanisms of HCMV immune escape helps to find the strategy to inhibit HCMV replicate. CD8+ T cells play a critical role in the immune response to viral pathogens. However, the mechanisms of HCMV to evade the attack by CD8+ T cells remain largely unknown. Viral CXCL1 (vCXCL1) is the production of HCMV UL146 gene. Here, we found that vCXCL1 promoted the resistance of hepatic cells to CD8+ T cells. vCXCL1 increased the levels of PD-L1 protein expression and mRNA expression. VCXCL1 enhanced the binding of STAT3 transcription factor to the promoter of PD-L1 and increased the activity of PD-L1 promoter. Furthermore, down-regulation of PD-L1 reduced the effects of vCXCL1 on the resistance of hepatic cells to CD8+ T cells. Taken together, vCXCL1 promotes the resistance of hepatic cells to CD8+ T cells through up-regulation of PD-L1. This finding might provide a new mechanism of HCMV immune escape.

The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses.

The chemokine CXCL14 is a highly conserved, homeostatic chemokine that is constitutively expressed in skin epithelia. Responsible for immune cell recruitment and maturation, as well as impacting epithelial cell motility, CXCL14 contributes to the establishment of immune surveillance within normal epithelial layers. Furthermore, CXCL14 is critical to upregulating major histocompatibility complex class I expression on tumor cells. Given these important roles, CXCL14 is often dysregulated in several types of carcinomas including cervical, colorectal, endometrial, and head and neck cancers. Its disruption has been shown to limit critical antitumor immune regulation and is correlated to poor patient prognosis. However, other studies have found that in certain cancers, namely pancreatic and some breast cancers, overexpression of stromal CXCL14 correlates with poor patient survival due to increased invasiveness. Contributing to the ambiguity CXCL14 plays in cancer is that the native CXCL14 receptor remains uncharacterized, although several candidate receptors have been proposed. Despite the complexity of CXCL14 functions, it remains clear that this chemokine is a key regulatory factor in cancer and represents a potential target for future cancer immunotherapies.

Chemokine CXCb1 stimulates formation of NETs in trunk kidney neutrophils of common carp.

Both in mammals and in fish, CXC chemokines activate leukocytes and regulate their migration both under normal physiological and inflammatory conditions. Moreover, in mammalian neutrophils CXC chemokines also stimulate the formation of neutrophil extracellular traps (NETs). Here, we investigated the effects of recombinant carp CXCL8s and CXCb1 on NET formation in neutrophils from the head (HK) and trunk (TK) kidney of carp. We found that neither recombinant CXCL8s nor CXCb1 stimulated DNA release in HK-derived neutrophils, while in TK-derived cells rcCXCb1 stimulated the release of NETs, composed of extracellular DNA co-localized with citrulline H3 histone and neutrophil elastase. Furthermore, CXCb1-induced NET release required NADPH oxidase activity, while it did not change upon treatment with CXCR inhibitors. In conclusion, we demonstrated, for the first time in fish, that CXCb1 chemokine induces formation of NETs in TK-derived neutrophils and this process is ROS-dependent. The difference between HK and TK-derived neutrophils is probably related to differences in the maturation state of these cells.

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis-Translation of Pathogenic Fundamentals Into an In Vitro Model.

Interface dermatitis is a histopathological pattern mirroring a distinct cytotoxic immune response shared by a number of clinically diverse inflammatory skin diseases amongst which lichen planus and cutaneous lupus erythematosus are considered prototypic. Interface dermatitis is characterized by pronounced cytotoxic immune cell infiltration and necroptotic keratinocytes at the dermoepidermal junction. The initial inflammatory reaction is established by cytotoxic immune cells that express CXC chemokine receptor 3 and lesional keratinocytes that produce corresponding ligands, CXC motif ligands 9/10/11, recruiting the effector cells to the site of inflammation. During the resulting anti-epithelial attack, endogenous immune complexes and nucleic acids are released from perishing keratinocytes, which are then perceived by the innate immune system as danger signals. Keratinocytes express a distinct signature of pattern recognition receptors and binding of endogenous nucleic acid motifs to these receptors results in interferon-mediated immune responses and further enhancement of CXC chemokine receptor 3 ligand production. In this perspective article, we will discuss the role of innate nucleic acid sensing as a common mechanism in the perpetuation of clinically heterogeneous diseases featuring interface dermatitis based on own data and a review of the literature. Furthermore, we will introduce a keratinocyte-specific in vitro model of interface dermatitis as follows: Stimulation of human keratinocytes with endogenous nucleic acids alone and in combination with interferon gamma leads to pronounced production of distinct cytokines, which are essential in the pathogenesis of interface dermatitis. This experimental approach bears the capability to investigate potential therapeutics in this group of diseases with unmet medical need.

A novel bovine CXCL15 gene in the GRO chemokine gene cluster.

In our previous transcriptomic studies using DNA microarray analysis, a probe designed from an unknown expressed sequence tag (EST) showed significant differential gene expression in the pharyngeal epithelia. The objectives of this study are to annotate the gene sequence and compare the gene transcription levels among different bovine tissues based on our published microarray data. The gene transcribing the EST contains a 90-amino-acid protein sequence. The results of bioinformatic analyses using comparative genetics, multiple sequence alignments, phylogenetic analysis and promoter sequence analysis indicated that this gene is a novel ELR+ CXCL gene orthologous to mouse CXCL15. The gene is highly conserved in ruminants and exists in many other mammals but not in chickens, primates or pigs. Phylogenetic analysis and gene structures showed that CXCL15 is closer to CXCL8 than to other ELR+ CXCLs. Our microarray data show that bovine CXCL15 expression was higher in laser capture micro-dissected bovine pharyngeal epithelia than in the whole pharyngeal tissues, which agrees with the expression in mice. However, unlike the high expression in the mouse lung, our results showed that the bovine nasal turbinate, dorsal nasopharynx, dorsal soft palate and tongue expressed higher levels of CXCL15 than the lung and skins. Promoter analysis showed that ruminants have more immune-related transcription factor binding sites in the proximal promoters of CXCL15 than mouse. CXCL15 has previously only been reported in mice and has neutrophil chemotactic activity. Given the critical roles of neutrophils in innate immunity, this study provides useful information for further characterization of bovine CXCL15.

Foam Cell-Derived CXCL14 Muti-Functionally Promotes Atherogenesis and Is a Potent Therapeutic Target in Atherosclerosis.

CXC chemokine family has been related to atherogenesis for long. However, the relationship between CXCL14 and atherogenesis is still unclear. This study preliminarily detected CXCL14 expression at foam cells in atherosclerosis specimens by immunohistochemistry. In vitro foam cells were derived from THP-1 after phorbol-12-myristate-13-acetate (PMA) and oxidized low-density lipoprotein (ox-LDL) stimulation. Immunoblotting and qPCR convinced CXCL14 expression variation during foam cell formation. We further demonstrated that ox-LDL regulated CXCL14 expression by AP-1. AP-1 could bind to CXCL14 promoter and up-regulate CXCL14 mRNA expression. Besides, CXCL14 promoted THP-1 migration, macrophage lipid phagocytosis, and smooth muscle cell migration as well as proliferation mainly via the ERK1/2 pathway. Additionally, a CXCL14 peptide-induced immune therapy showed efficacy in ApoE-/- mouse model. In conclusion, our study demonstrated that CXCL14 is highly up-regulated during foam cell formation and promotes atherogenesis in various ways. CXCL14 may be a potent therapeutic target for atherosclerosis.

Group 1 innate lymphoid cells are involved in the progression of experimental anti-glomerular basement membrane glomerulonephritis and are regulated by peroxisome proliferator-activated receptor α.

Innate lymphoid cells play an important role in the early effector cytokine-mediated response. In Wistar Kyoto rats, CD8+ non-T lymphocytes (CD8+Lym) infiltrate into glomeruli during the development of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Here, we examined the profiles and roles of CD8+Lym in anti-GBM glomerulonephritis. The regulation of CD8+Lym by peroxisome proliferator-activated receptor (PPAR)-α in anti-GBM glomerulonephritis was also evaluated. Glomerular infiltrating CD8+Lym were lineage-negative cells that showed markedly high expression of IFN-γ and T-bet mRNAs but not Eomes, indicating these cells are group 1 innate lymphoid cells. In anti-GBM glomerulonephritis, the glomerular mRNAs of innate lymphoid cell-related cytokines (IFN-γ and TNF-α) and chemokines (CXCL9, CXCL10, and CXCL11) are significantly increased. Treatment with a PPARα agonist ameliorated renal injury, with reduced expression of these mRNAs. In vitro, enhanced IFN-γ production from innate lymphoid cells upon IL-12 and IL-18 stimulation was reduced by the PPARα agonist. Moreover, CXCL9 mRNA in glomerular endothelial cells and CXCL9, CXCL10, and CXCL11 mRNAs in podocytes and macrophages were upregulated by IFN-γ, whereas the PPARα agonist downregulated their expression. We also detected the infiltration of innate lymphoid cells into glomeruli in human anti-GBM glomerulonephritis. Thus, innate lymphoid cells are involved in the progression of anti-GBM glomerulonephritis and regulated directly or indirectly by PPARα. Our findings suggest that innate lymphoid cells could serve as novel therapeutic targets for anti-GBM glomerulonephritis.

CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression.

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immune-dependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8+ T cells are required for CXCL14-mediated tumor suppression. Using a CD8+ T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8+ T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8+ T-cell responses to suppress HPV-positive HNC.

The important role played by chemokines influence the clinical outcome of Helicobacter pylori infection.

The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.

Recruitment of MAIT Cells to the Intervillous Space of the Placenta by Placenta-Derived Chemokines.

The intervillous space of the placenta is a part of the fetal-maternal interface, where maternal blood enters to provide nutrients and gas exchange. Little is known about the maternal immune cells at this site, which are in direct contact with fetal tissues. We have characterized the T cell composition and chemokine profile in paired intervillous and peripheral blood samples from healthy mothers giving birth following term pregnancies. Mucosal-associated invariant T (MAIT) cells and effector memory (EM) T cells were enriched in the intervillous blood compared to peripheral blood, suggesting that MAIT cells and other EM T cells home to the placenta during pregnancy. Furthermore, pregnant women had lower proportions of peripheral blood MAIT cells compared to non-pregnant women. The levels of several chemokines were significantly higher in intervillous compared to peripheral blood, including macrophage migration inhibitory factor (MIF), CXCL10, and CCL25, whereas CCL21, CCL27 and CXCL12 were lower. Migration assays showed that MAIT cells and EM T cells migrated toward conditioned medium from placental explants. A multivariate factor analysis indicated that high levels of MIF and CCL25 were associated with high proportions of MAIT cells in intervillous blood. Blocking of MIF or a combination of MIF, CCL25, and CCL20 in migration assays inhibited MAIT cell migration toward placenta conditioned medium. Finally, MAIT cells showed migratory capacities toward recombinant MIF. Together, these findings indicate that term placental tissues attract MAIT cells, and that this effect is at least partly mediated by MIF.

BATF3-dependent dendritic cells drive both effector and regulatory T-cell responses in bacterially infected tissues.

The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.