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Introduction: Most T lymphocytes, including regulatory T cells, express the CD27 costimulatory receptor in steady state conditions. There is evidence that CD27 engagement on conventional T lymphocytes favors the development of Th1 and cytotoxic responses in mice and humans, but the impact on the regulatory lineage is unknown. Methods: In this report, we examined the effect of constitutive CD27 engagement on both regulatory and conventional CD4+ T cells in vivo, in the absence of intentional antigenic stimulation. Results: Our data show that both T cell subsets polarize into type 1 Tconvs or Tregs, characterized by cell activation, cytokine production, response to IFN-g and CXCR3-dependent migration to inflammatory sites. Transfer experiments suggest that CD27 engagement triggers Treg activation in a cell autonomous fashion. Conclusion: We conclude that CD27 may regulate the development of Th1 immunity in peripheral tissues as well as the subsequent switch of the effector response into long-term memory. [ABSTRACT FROM AUTHOR]

Adipose tissue homeostasis relies on the interplay between several regulatory lineages, such as type 2 innate lymphoid cells (ILC2s), T helper 2 (Th2) cells, regulatory T cells, eosinophils, and type 2 macrophages. Among them, ILC2s are numerically the dominant source of type 2 cytokines and are considered as major regulators of adiposity. Despite the overlap in immune effector molecules and sensitivity to alarmins (thymic stromal lymphopoietin and interleukin-33) between ILC2s and resident memory Th2 lymphocytes, the role of the adaptive axis of type 2 immunity remains unclear. We show that mice deficient in CD27, a member of the tumor necrosis factor receptor superfamily, are more resistant to obesity and associated disorders. A comparative analysis of the CD4 compartment of both strains revealed higher numbers of fat-resident memory Th2 cells in the adipose tissue of CD27 knockout mice, which correlated with decreased programmed cell death protein 1-induced apoptosis. Our data point to a non-redundant role for Th2 lymphocytes in obesogenic conditions. [Display omitted] • CD27 upregulates PD-1 expression on fat-resident Th2 cells in an intrinsic manner • PD-1 shifts the fate of Th2 toward activation-induced cell death • CD27 deletion results in increased adaptive type 2 immunity in the adipose tissue • The adaptive axis of type 2 immunity protects against obesity and associated disorders The function of Th2 is impaired during obesity. Here, Englebert et al. show that CD27-deficient mice are resistant to obesity and metabolic disorders. This protection correlates with increased Th2 numbers and cytokine production, which sustain visceral eosinophils and RELMα+ macrophages. The data point to a role of PD-1 in this process. [ABSTRACT FROM AUTHOR]

Monocytes play a major role in the defense against pathogens. They are rapidly mobilized to inflamed sites where they exert both proinflammatory and regulatory effector functions. It is still poorly understood how this dynamic and exceptionally plastic system is controlled at the molecular level. Herein, we evaluated the differentiation process that occurs in Ly6Chi monocytes during oral infection by Toxoplasma gondii. Flow cytometry and single-cell analysis revealed distinct activation status and gene expression profiles in the bone marrow, the spleen and the lamina propria of infected mice. We provide further evidence that acquisition of effector functions, such as the capacity to produce interleukin-27, is accompanied by distinct waves of epigenetic programming, highlighting a role for STAT1/IRF1 in the bone marrow and AP-1/NF-κB in the periphery. This work broadens our understanding of the molecular events that occur in vivo during monocyte differentiation in response to inflammatory cues. Detavernier et al. show that localized waves of epigenetic programming regulate the differentiation process of Ly6Chi monocytes during oral infection by Toxoplasma gondii, which are dominated by STAT1 in the bone marrow and AP-1/NF-kB in the periphery. This study provides insight into how monocytes are differentiated in response to inflammatory cues. [ABSTRACT FROM AUTHOR]

The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked ( IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells ( tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/ CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4+ T cells that was strictly reliant on a functional CD27/ CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells ( DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses. [ABSTRACT FROM AUTHOR]

The transcription factor hypoxia inducible factors ( HIF)-1 functions as a master regulator of oxygen homeostasis. There is increasing evidence that HIF has an essential role to prevent tissue damage in physiological and pathological situations in which cells are deprived of O2. Here, we review the effects of decreased oxygen supply on the innate and adaptive immune responses in the gut and in solid tumors in which the oxygenation profile correlates with the grade of inflammation. Data in the literature indicate that some tumors may co-opt immune mechanisms induced by HIF-1 to promote their survival and proliferation. By contrast, HIF-1 stabilization would have a beneficial effect in the intestinal tract as it would dampen inflammation and promote its resolution. Therefore, stabilization of HIF-1 in hypoxia may have opposite effects on the integrity of the host, depending on the tissue microenvironment. [ABSTRACT FROM AUTHOR]

There is increasing evidence that the effect of chemotherapy on tumor growth is not cell autonomous but relies on the immune system. The objective of this study was therefore to decipher the cellular and molecular mechanisms underlying the role of innate and adaptive immunity in chemotherapy-induced tumor rejection. Treatment of DBA/2 mice bearing P815 mastocytoma with cyclophosphamide induced rejection and long-term protection in a CD4- and CD8-dependent manner. A population of inflammatory-type dendritic cells was dramatically expanded in the lymph nodes of mice that rejected the tumor and correlated with CD4-dependent infiltration, in tumor bed, of tumor-specific CD8+ T lymphocytes. Our data point to a major role of CD4+ T cells in inducing chemokine expression in the tumor, provoking migration of tumor-specific CXCR3+ CD8+ T lymphocytes. Importantly, the analysis of CD8+ T cells specific to P1A/H-2Ld and P1E/H-2Kd revealed that cyclophosphamide altered the P815-specific CD8 T repertoire by amplifying the response specific to the mutated P1E antigen. [ABSTRACT FROM AUTHOR]

Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes. [ABSTRACT FROM AUTHOR]

Natural CD4 [ABSTRACT FROM AUTHOR]

CD4CD25 T reg cells are critical for peripheral tolerance and prevention of autoimmunity. Here we show that CD4CD25 T reg also regulate the magnitude of humoral responses against a panel of T-dependent antigens of foreign origin during both primary and secondary immune responses. Depletion of CD4CD25 T cells leads to increased antigen-specific antibody production and affinity maturation but does not affect T-independent B cell responses, suggesting that CD4CD25 T reg exert a feedback mechanism on non-self antigen-specific antibody secretion by dampening the T cell help for B cell activation. Moreover, we show that CD4CD25 T reg also suppress in vitro B cell immunoglobulin production by inhibiting CD4CD25 T cell help delivery, and that blockade of TGF-β activity abolishes this suppression. [ABSTRACT FROM AUTHOR]

There is increasing evidence that dendritic cells (DC) display opposite functions in the immune system, as they may induce immunity or tolerance depending on intrinsic and environmental factors. In mice, adoptive transfer of mature DC pulsed extracorporeally with antigen induces the development of antigen-specific Th1- and Th2-type CD4 cells. In this work, we compared the adjuvant properties of immature (freshly isolated) and mature (cultured) splenic DC in vivo. Our data show that injection of either cell population induces the clonal expansion of CD4 T cells but that only mature DC trigger their differentiation into effector cells producing IFN-γ. In contrast, transfer of immature DC provokes the development of intermediates in the differentiation process, similar to the central memory cells. These observations, together with data in the literature, suggest that DC may induce tolerance, memory, or immunity depending on their maturationstate. [ABSTRACT FROM AUTHOR]

Summary Recent observations clearly highlight the critical role of type 2 innate lymphoid cells in maintaining the homeostasis of adipose tissues in humans and mice. This cell population promotes beiging and limits adiposity directly and indirectly by sustaining a Th2-prone environment enriched in eosinophils and alternatively activated macrophages. Accordingly, the number and function of type 2 innate lymphoid cells (ILC2s) are strongly impaired in obese individuals. In this work, we identify the PD-1-PD-L1 pathway as a factor leading to ILC2 destabilization upon high-fat feeding resulting in impaired tissue metabolism. Tumor necrosis factor (TNF) appears to play a central role, triggering interleukin-33 (IL-33)-dependent PD-1 expression on ILC2s and recruiting and activating PD-L1hi M1 macrophages. PD-1 blockade partially restores the type 2 innate axis, raising the possibility of restoring tissue homeostasis. Graphical Abstract Highlights • PD-1 is upregulated on ILC2s in adipose tissue of obese mice • PD-1 expression is increased in a TNF- and IL-33-dependent manner • PD-1 correlates with impaired ILC2 function in the presence of PD-L1+ macrophages • PD-1 blockade ameliorates glucose tolerance and adaptation to environmental cold The function of ILC2s is compromised during obesity. Here, Oldenhove et al. show that ILC2 inhibition is mediated by the PD-1-PD-L1 pathway. PD-1 blockade in obese mice improved ILC2 function, reinforced type 2 innate responses, and promoted tissue homeostasis. PD-1 may therefore represent a target for immune intervention in obesity-associated disorders. [ABSTRACT FROM AUTHOR]