The Journal of Immunology

Establishing High Dimensional Immune Signatures from Peripheral Blood via Mass Cytometry in a Discovery Cohort of Stage IV Melanoma Patients [SYSTEMS IMMUNOLOGY]

The identification of blood-borne biomarkers correlating with melanoma patient survival remains elusive. Novel techniques such as mass cytometry could help to identify melanoma biomarkers, allowing simultaneous detection of up to 100 parameters. However, the evaluation of multiparametric data generated via time-of-flight mass cytometry requires novel analytical techniques because the application of conventional gating strategies currently used in polychromatic flow cytometry is not feasible. In this study, we have employed 38-channel time-of-flight mass cytometry analysis to generate comprehensive immune cell signatures using matrix boolean analysis in a cohort of 28 stage IV melanoma patients and 17 controls. Clusters of parameters were constructed from the abundance of cellular phenotypes significantly different between patients and controls. This approach identified patient-specific combinatorial immune signatures consisting of high-resolution subsets of the T cell, NK cell, B cell, and myeloid compartments. An association with superior survival was characterized by a balanced distribution of myeloid-derived suppressor cell-like and APC-like myeloid phenotypes and differentiated NK cells. The results of this study in a discovery cohort of melanoma patients suggest that multifactorial immune signatures have the potential to allow more accurate prediction of individual patient outcome. Further investigation of the identified immune signatures in a validation cohort is now warranted.

MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation [INNATE IMMUNITY AND INFLAMMATION]

The IL-17 family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti–IL-17A Abs were recently approved to treat human psoriasis. Little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. In this article, we show that the endoribonuclease MCP-1–induced protein 1 (MCPIP1; also known as regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency (Zc3h12a+/–) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a+/– mice was associated with elevated expression of IL-17A– and IL-17C–dependent genes, as well as with increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a+/– mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in nonhematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a+/–Il17ra–/– mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a+/–Il17a–/– and Zc3h12a+/–Il17c–/– mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a–/– keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, to our knowledge, MCPIP1 is the first described negative regulator of IL-17C signaling.

Epigenetic Networks Regulate the Transcriptional Program in Memory and Terminally Differentiated CD8+ T Cells [SYSTEMS IMMUNOLOGY]

Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8+ T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8+ T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8+ T cell maintenance and T cell terminal differentiation.

Cutting Edge: LL-37-Mediated Formyl Peptide Receptor-2 Signaling in Follicular Dendritic Cells Contributes to B Cell Activation in Peyers Patch Germinal Centers [CUTTING EDGE]

Peyer’s patches (PPs) are the major mucosal immune-inductive site, and germinal centers (GCs) in PPs determine the quality of the Abs produced. PP GCs are continuously induced by the gut microbiota, and their maintenance contributes to the induction of strong IgA responses to Ags. In this study, we investigated the role of formyl peptide receptor (FPR)-mediated signaling in the maintenance of PP GCs, because FPRs recognize the microbiota and initiate an innate immune response by chemotaxis. We found that follicular dendritic cells (FDCs), a key organizer of B cell follicles and GCs in mucosal immunity, express Fpr2. Additionally, Fpr2-mediated signaling in PP FDCs promoted Cxcl13 and B cell activating factor expression, as well as B cell proliferation and activation. Therefore, we suggest that Fpr2-mediated signaling in FDCs plays a key role in GC maintenance in PPs and results in an Ag-specific IgA response in the gut mucosal immune compartment.

The Neonatal Window of Opportunity: Setting the Stage for Life-Long Host-Microbial Interaction and Immune Homeostasis [BRIEF REVIEWS]

The existence of a neonatal window was first highlighted by epidemiological studies that revealed the particular importance of this early time in life for the susceptibility to immune-mediated diseases in humans. Recently, the first animal studies emerged that present examples of early-life exposure–triggered persisting immune events, allowing a detailed analysis of the factors that define this particular time period. The enteric microbiota and the innate and adaptive immune system represent prime candidates that impact on the pathogenesis of immune-mediated diseases and are known to reach a lasting homeostatic equilibrium following a dynamic priming period after birth. In this review, we outline the postnatal establishment of the microbiota and maturation of the innate and adaptive immune system and discuss examples of early-life exposure–triggered immune-mediated diseases that start to shed light on the critical importance of the early postnatal period for life-long immune homeostasis.

Host-Microbiota Interactions Shape Local and Systemic Inflammatory Diseases [BRIEF REVIEWS]

Recent advances in understanding how the mammalian immune system and intestinal microbiota functionally interact have yielded novel insights for human health and disease. Modern technologies to quantitatively measure specific members and functional characteristics of the microbiota in the gastrointestinal tract, along with fundamental and emerging concepts in the field of immunology, have revealed numerous ways in which host-microbiota interactions proceed beneficially, neutrally, or detrimentally for mammalian hosts. It is clear that the gut microbiota has a strong influence on the shape and quality of the immune system; correspondingly, the immune system guides the composition and localization of the microbiota. In the following review, we examine the evidence that these interactions encompass homeostasis and inflammation in the intestine and, in certain cases, extraintestinal tissues. Lastly, we discuss translational therapies stemming from research on host-microbiota interactions that could be used for the treatment of chronic inflammatory diseases.

Microbiome-Modulated Metabolites at the Interface of Host Immunity [BRIEF REVIEWS]

The mammalian gastrointestinal tract and associated mucosal immune system harbor a large repertoire of metabolites of prokaryotic and eukaryotic origin that play important roles in eukaryotic development and physiology. These often bioactive small molecules originate from nutrition- and environmental-related sources, or are endogenously produced and modulated by the host and its microbiota. A complex network of interactions exists between the intestinal mucosal immune system and the microbiota. This intimate cross-talk may be driven by metabolite secretion and signaling, and features profound influences on host immunity and physiology, including the endocrine, metabolic, and nervous system function in health and disease. Alterations in microbiome-associated metabolite levels and activity are implicated in the pathogenesis of a growing number of illnesses. In this review we discuss the origin and influence of microbiome-modulated metabolites, with an emphasis on immune cell development and function. We further highlight the emerging data potentially implicating metabolite misbalance with host-microbiome–associated disease.

The Influence of the Microbiome on Allergic Sensitization to Food [BRIEF REVIEWS]

The alarming increase in the incidence and severity of food allergies has coincided with lifestyle changes in Western societies, such as dietary modifications and increased antibiotic use. These demographic shifts have profoundly altered the coevolved relationship between host and microbiota, depleting bacterial populations critical for the maintenance of mucosal homeostasis. There is increasing evidence that the dysbiosis associated with sensitization to food fails to stimulate protective tolerogenic pathways, leading to the development of the type 2 immune responses that characterize allergic disease. Defining the role of beneficial allergy-protective members of the microbiota in the regulation of tolerance to food has exciting potential for new interventions to treat dietary allergies by modulation of the microbiota.

The Influence of the Microbiome on Type 1 Diabetes [BRIEF REVIEWS]

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β cells. The rapid rise in T1D incidence during the past 50 y suggests environmental factors contribute to the disease. The trillion symbiotic microorganisms inhabiting the mammalian gastrointestinal tract (i.e., the microbiota) influence numerous aspects of host physiology. In this study we review the evidence linking perturbations of the gut microbiome to pancreatic autoimmunity. We discuss data from rodent models demonstrating the essential role of the gut microbiota on the development and function of the host’s mucosal and systemic immune systems. Furthermore, we review findings from human longitudinal cohort studies examining the influence of environmental and lifestyle factors on microbiota composition and pancreatic autoimmunity. Taken together, these data underscore the requirement for mechanistic studies to identify bacterial components and metabolites interacting with the innate and adaptive immune system, which would set the basis for preventative or therapeutic strategies in T1D.

LASID Latin American Society for Immunodeficiencies Ir arriba