Adipose-tissue Treg cells restrain differentiation of stromal adipocyte precursors to promote insulin sensitivity and metabolic homeostasis.

Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect.

Regulatory T cells play a crucial role in maintaining sperm tolerance and male fertility.

Regulatory T cells (Tregs) modulate tissue homeostatic processes and immune responses. Understanding tissue-Treg biology will contribute to developing precision-targeting treatment strategies. Here, we show that Tregs maintain the tolerogenic state of the testis and epididymis, where sperm are produced and mature.

Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1.

Although natural killer (NK) cells infiltrate clear cell renal cell carcinomas (ccRCC), the most frequent malignancy of the kidney, tumor progression suggests that they become dysfunctional. As ccRCC-driven subversion of NK cell effector functions is usually accompanied by phenotypic changes, analysis of such alterations might lead to the identification of novel biomarkers and/or targets in immuno-oncology. Consequently, we performed a phenotypic analysis of peripheral blood NK cells (PBNK) and tumor-infiltrating NK cells (TINK) from ccRCC patients.

Visceral adipose tissue mesenchymal stromal cells in the intersection of immunology and metabolism.

Visceral adipose tissue (VAT) is now recognized as an endocrine organ that plays a key role in organismal homeostasis by integrating metabolic and immunological aspects. In healthy individuals, this fat depot participates in the storage and release of lipids as per physiological demand, while maintaining a local anti-inflammatory environment. In this regard, recent findings highlight the pivotal role of distinct subtypes of mesenchymal stromal cells (mSCs) as orchestrators of metabolic homeostasis by engendering adipocytes to sustain adequate lipid storage as well as immune regulators via cross-talk with specialized tissue-resident immunocytes, especially regulatory T cells (Tregs) and group 2 innate lymphoid cells (ILC2s) to prevent the development of local inflammation.

From initial segment to cauda: a regional characterization of mouse epididymal CD11c mononuclear phagocytes based on immune phenotype and function.

Successful sperm maturation and storage rely on a unique immunological balance that protects the male reproductive organs from invading pathogens and spermatozoa from a destructive autoimmune response. We previously characterized one subset of mononuclear phagocytes (MPs) in the murine epididymis, CX3CR1 cells, emphasizing their different functional properties. This population partially overlaps with another subset of understudied heterogeneous MPs, the CD11c cells.

Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein.

Background: Natural killer and cytotoxic CD8 T cells are major players during antitumor immunity. They express NKG2D, an activating receptor that promotes tumor elimination through recognition of the MHC class I chain-related proteins A and B (MICA and MICB). Both molecules are overexpressed on a great variety of tumors from different tissues, making them attractive targets for immunotherapy.

Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice.

Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery, or exposure to nephrotoxins. Here, using a murine renal ischemia/reperfusion injury (IRI) model, we show that intercalated cells (ICs) rapidly adopted a proinflammatory phenotype after IRI. Wwe demonstrate that during the early phase of AKI either blockade of the proinflammatory P2Y14 receptor located on the apical membrane of ICs or ablation of the gene encoding the P2Y14 receptor in ICs (a) inhibited IRI-induced increase of chemokine expression in ICs, (b) reduced neutrophil and monocyte renal infiltration, (c) reduced the extent of kidney dysfunction, and (d) attenuated proximal tubule damage.

Visceral adipose tissue Tregs and the cells that nurture them.

Visceral adipose tissue (VAT) is a primary site for storage of excess energy, but it also serves as an important endocrine organ that impacts organismal metabolism. Chronic, low-grade inflammation of VAT, and eventually systemically, is one of the major drivers of obesity-associated insulin resistance and metabolic abnormalities. A unique population of regulatory T cells (Tregs), with a distinct transcriptional profile and antigen receptor repertoire resides in VAT, keeps inflammation in check and regulates organismal metabolism.

Sex-specific adipose tissue imprinting of regulatory T cells.

Adipose tissue is an energy store and a dynamic endocrine organ. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes.

Neuronal, stromal, and T-regulatory cell crosstalk in murine skeletal muscle.

A distinct population of Foxp3CD4 regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33 mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate.

Region-specific transcriptomic and functional signatures of mononuclear phagocytes in the epididymis.

In the epididymis, prevention of autoimmune responses against spermatozoa and simultaneous protection against pathogens is important for male fertility. We have previously shown that mononuclear phagocytes (MPs) are located either in the epididymal interstitium or in close proximity to the epithelium. In the initial segments (IS), these 'intraepithelial' MPs extend slender luminal-reaching projections between epithelial cells.

Low Doses of CPS49 and Flavopiridol Combination as Potential Treatment for Advanced Prostate Cancer.

Due to some inconsistencies in the figures provided by the first author that have come to light, and after a thorough investigation we would like to retract our paper: "Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer. By: Zalazar F, De Luca P, Gardner K, Figg WD, Meiss R, Spallanzani RG, Vallecorsa P, Elguero B, Cotignola J, Vazquez E, De Siervi A. Curr.

Novel role of proton-secreting epithelial cells in sperm maturation and mucosal immunity.

Epithelial cells are immune sensors and mediators that constitute the first line of defense against infections. Using the epididymis, a model for studying tubular organs, we uncovered a novel and unexpected role for professional proton-secreting 'clear cells' in sperm maturation and immune defense. The epididymal epithelium participates in the maturation of spermatozoa via the establishment of an acidic milieu and transfer of proteins to sperm cells, a poorly characterized process.

Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors.

Regulatory T cells (T) are key brakes on the visceral adipose tissue (VAT) inflammation that regulates local and systemic metabolic tenor. Breakdown of this regulation promotes type 2 diabetes. The cytokine IL-33 expands and sustains the unique T population residing within VAT.

TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype.

Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario.

Interleukin (IL)-23 Stimulates IFN-γ Secretion by CD56 Natural Killer Cells and Enhances IL-18-Driven Dendritic Cells Activation.

Interleukin (IL)-23 is a member of the IL-12 family of cytokines that, as the other members of this family, is secreted by monocytes, macrophages, and dendritic cells (DC) upon recognition of bacterial, viral, and fungal components. IL-23 is critical during immunity against acute infections, and it is also involved in the development of autoimmune diseases. Although immunoregulatory effects of IL-23 on mouse natural killer (NK) cells have been described, the effect of IL-23 on human NK cells remains ill-defined.

Complexity of Complement Resistance Factors Expressed by Needed for Survival in Human Serum.

is a bacterial pathogen with increasing impact in healthcare settings, due in part to this organism's resistance to many antimicrobial agents, with pneumonia and bacteremia as the most common manifestations of disease. A significant proportion of clinically relevant strains are resistant to killing by normal human serum (NHS), an observation supported in this study by showing that 12 out of 15 genetically diverse strains of are resistant to NHS killing. To expand our understanding of the genetic basis of serum resistance, a transposon (Tn) sequencing (Tn-seq) approach was used to identify genes contributing to this trait.

Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC.

Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice.

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells.

Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8(+) T cells, leading to reduced memory responses.

Regulatory Dendritic Cells Restrain NK Cell IFN-γ Production through Mechanisms Involving NKp46, IL-10, and MHC Class I-Specific Inhibitory Receptors.

Cross-talk between mature dendritic cells (mDC) and NK cells through the cell surface receptors NKp30 and DNAM-1 leads to their reciprocal activation. However, the impact of regulatory dendritic cells (regDC) on NK cell function remains unknown. As regDC constrain the immune response in different physiological and pathological conditions, the aim of this work was to investigate the functional outcome of the interaction between regDC and NK cells and the associated underlying mechanisms.

Low doses of CPS49 and flavopiridol combination as potential treatment for advanced prostate cancer.

Prostate cancer (PCa) still ranks as the second most frequently diagnosed cancer and metastatic castration resistant prostate cancer (CRPC) is a foremost cause of men cancer death around the world. The aim of this work was to investigate the selectivity and efficacy of new drug combinations for CRPC. We combined three compounds: paclitaxel (PTX: taxane that inhibits microtubule polymerization); 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole- 1,3(2H)-dione (CPS49; redox-reactive thalidomide analog with anti-angiogenic properties) and flavopiridol (flavo: semisynthetic flavonoid that inhibits cyclin dependent kinases).

IL-27 stimulates human NK-cell effector functions and primes NK cells for IL-18 responsiveness.

IL-27, a member of the IL-12 family of cytokines, is produced by APCs, and displays pro- and anti-inflammatory effects. How IL-27 affects human NK cells still remains unknown. In this study, we observed that mature DCs secreted IL-27 and that blockade of IL-27R (CD130) reduced the amount of IFN-γ produced by NK cells during their coculture, showing the importance of IL-27 during DC-NK-cell crosstalk.

Expansion of CD11b(+)Ly6G (+)Ly6C (int) cells driven by medroxyprogesterone acetate in mice bearing breast tumors restrains NK cell effector functions.

The progesterone analog medroxyprogesterone acetate (MPA) is widely used as a hormone replacement therapy in postmenopausal women and as contraceptive. However, prolonged administration of MPA is associated with increased incidence of breast cancer through ill-defined mechanisms. Here, we explored whether exposure to MPA during mammary tumor growth affects myeloid-derived suppressor cells (MDSCs; CD11b(+)Gr-1(+), mostly CD11b(+)Ly6G(+)Ly6C(int) and CD11b(+)Ly6G(-)Ly6C(high) cells) and natural killer (NK) cells, potentially restraining tumor immunosurveillance.

Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression.

HDACi are being used as a novel, therapeutic approach for leukemias and other hematological malignancies. However, their effect on immune cells remains ill-defined, as HDACi may impair immune surveillance. In this work, we demonstrate that TSA, VPA, and NaB inhibited IFN-γ production by CD56(dim) and CD56(bright) NK cells and NK cell-mediated cytotoxicity against K562 target cells.