Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Regulatory T Cells and Immune Tolerance

Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme

CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

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Differentiation of Effector CD4 T Cell Populations

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell–mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

Regulatory T Cells: Mechanisms of Differentiation and Function

The vertebrate jaw is a versatile feeding apparatus that facilitated explosive diversification. Its functions require a joint between the upper and lower jaws, so jaw joint defects — such as osteoarthritis or even ankylosis — are often highly disruptive and difficult to study. To describe consequences of jaw joint dysfunction, we engineered two independent null alleles of a single jaw-joint marker gene, nkx3.2, in zebrafish. The mutations caused the fish to become functionally jawless via a fusion between the upper and lower jaw cartilages (ankylosis). Surviving to adulthood despite lacking jaw joints, nkx3.2 mutants accommodate this defect by: a) remodeling their skulls drastically from juvenile to adult stages; and b) altering their feeding behaviors from suction to ram feeding. As a result of the remodeling, nkx3.2 mutants developed superficial similarities to the skull shapes observed in two lineages of ancient jawless vertebrates (anaspids and furcacaudiform thelodonts), including: a fixed open gape, reduced snout, and enlarged branchial region. However, no homology exists in individual skull elements between these taxa, and most of the modified elements in the mutant zebrafish occur outside known expression domains of nkx3.2. Therefore, we interpret the adult nkx3.2 phenotype not as a reversal to an ancestral state, but as convergence due to similar functional requirement of feeding without mobile jaws. This remarkable convergence underscores jaw joint functions as a powerful constraint during the development of jawed vertebrate skulls, which implies that functionally viable morphological patterns are finite, with or without functional jaws. Because nkx3.2 null zebrafish display prominent joint ankylosis, drastically modified skull shape, and altered feeding behaviors, these mutants provide a unique model with which to investigate mechanisms of skeletal remodeling and joint diseases.

https://biorxiv.org/content/biorxiv/early/2019/09/19/776351.full-text.pdf

nkx3.2 mutant zebrafish accommodate the jaw joint loss through a phenocopy of the head shapes of Paleozoic agnathans

<h3>Objectives</h3> Several studies have linked chronic inflammatory conditions such as Crohn's disease (CD) or inflammatory arthritis to increased risk for periodontal disease (PD). It is attractive to attribute this to increased circulating pro-inflammatory cytokine levels such as tumor necrosis factor-alpha (TNF-α). Women show a higher incidence of CD, and women with CD have a higher risk of developing PD. How sex differences affect disease susceptibility and how this might be linked to pro-inflammatory cytokines is not well understood. The TNFΔARE (TNFΔ/WT) mouse is an established model for CD and inflammatory arthritis. The prolonged and increased TNF-α production led to spontaneous development of these 2 inflammatory diseases from a young age. Here, we used this model to test sex prevalence and the role of circulating TNF-α in the development of PD. <h3>Study Design</h3> Both male and female TNFΔARE (TNFΔ/WT) and control WT mice were analyzed at 2 and 4 months of age for changes to the temporomandibular joint (TMJ), buccal mucosa, gingival epithelium, and alveolar bone. MicroCT scans were acquired using a Milabs U-CT scanner and analyzed using Avizo 9.1.1. Oral manifestations were analyzed using histology (hematoxylin & eosin, Tartrate-resistant acid phosphatase (TRAP), Safranin O) and immunofluorescence to assess proliferation (Ki67), inflammation (CD45), and bone remodeling (Sclerostin (SOST), Receptor activator of nuclear factor kappa-B ligand (RANKL)). <h3>Results</h3> Four-month-old but not 2-month-old TNFΔ/WT showed various oral manifestations associated with arthritis (TMJ) or CD (cobblestone mucosa). No evidence of active periodontal disease was found. Four-month-old female mice showed gingival hyperplasia, severe TMJ arthritis, malocclusion, and alveolar bone loss in the absence of other signs of PD (epithelial inflammation, bleeding). Four-month-old TNFΔ/WT male mice presented TMJ arthritis, cobblestone mucosa, lack of hyperplasia but limited presence of leukocytes at the gingival epithelium, periodontal ligament, and buccal mucosa. Other signs of PD (epithelial inflammation, bleeding) were also missing. <h3>Conclusions</h3> We present strong evidence that circulating TNF-α is not sufficient to induce PD. The role of TNF-α in oral tissues is complex. TMJ arthritis and malocclusion might trigger alveolar bone loss in female TNFΔARE mice in the absence of PD. Sex-specific differences in oral manifestations (hyperplasia vs cobblestone mucosa) might be directly related to local rather than systemic differences in TNF-α. 

Tnf alpha and sex prevalence of oral manifestations in chronic inflammatory diseases: it's complicated

Realistic mappings of genes to morphology are inherently multivariate on both sides of the equation. The importance of coordinated gene effects on morphological phenotypes is clear from the intertwining of gene actions in signaling pathways, gene regulatory networks, and developmental processes underlying the development of shape and size. Yet, current approaches tend to focus on identifying and localizing the effects of individual genes and rarely leverage the information content of high dimensional phenotypes. Here, we explicitly model the joint effects of biologically coherent collections of genes on a multivariate trait-craniofacial shape - in a sample of n = 1,145 mice from the Diversity Outbred (DO) experimental line. We use biological process gene ontology (GO) annotations to select skeletal and facial development gene sets and solve for the axis of shape variation that maximally covaries with gene set marker variation. We use our process-centered, multivariate genotype-phenotype (process MGP) approach to determine the overall contributions to craniofacial variation of genes involved in relevant processes and how variation in different processes corresponds to multivariate axes of shape variation. Further, we compare the directions of effect in phenotype space of mutations to the primary axis of shape variation associated with broader pathways within which they are thought to function. Finally, we leverage the relationship between mutational and pathway-level effects to predict phenotypic effects beyond craniofacial shape in specific mutants. We also introduce an online application which provides users the means to customize their own process-centered craniofacial shape analyses in the DO. The process-centered approach is generally applicable to any continuously varying phenotype and thus has wide-reaching implications for complex-trait genetics.

Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape.

INTRODUCTION: Bone Morphogenetic Proteins play multiple and important roles in embryonic development and homeostasis and tissue repair in adult tissues. In the adult or later stage embryos, systematic functional studies have so far been hampered by lack of mice that would allow conditional gene ablation, a prerequisite to overcome the early or complex phenotypes of straight null alleles. We present here the generation of conditional alleles for BMP-2 and BMP-7. Both molecules are highly conserved across mammalian species. Thus allele design is of prime importance, as particular care has to be taken not to create hypomorph alleles. For this reason, for targeting construct assembly we used Bacterial Homologous Recombination (BHR) on Bacterial Artificial Chromosomes (BAC), a technology that allows genome manipulation with base-pair precision and enabled us to take locus idiosyncrasies into consideration. For the generation of the conditional alleles we have adapted the classic two loxP-site strategy to BHR. Functional analysis in mice carrying these conditional alleles showed that they behave like null alleles following Cremediated recombination, making them suitable tools for in vivo studies.

Generation and characterization of conditional alleles for bmp-2 and bmp-7

The mammalian kidney is composed of thousands of nephrons that are formed through reiterative induction of a mesenchymal-to-epithelial transformation by a population of nephron progenitor cells. The number of nephrons in human kidneys ranges from several hundred thousand to nearly a million, and low nephron number has been implicated as a risk factor for kidney disease as an adult. Bmp7 is among a small number of growth factors required to support the proliferation and self-renewal of nephron progenitor cells, in a process that will largely determine the final nephron number. Once induced, each nephron begins as a simple tubule that undergoes extensive proliferation and segmental differentiation. Bmp7 is expressed both by nephron progenitor cells and the ureteric bud derivative branches that induce new nephrons. Here, we show that, in mice, Bmp7 expressed by progenitor cells has a major role in determining nephron number; nephron number is reduced to one tenth its normal value in its absence. Postnatally, Bmp7 also drives proliferation of the proximal tubule cells, and these ultimately constitute the largest segment of the nephron. Bmp7 appears to act through Smad 1,5,9(8), p38 and JNK MAP kinase. In the absence of Bmp7, nephrons undergo a hypertrophic process that involves p38. Following a global inactivation of Bmp7, we also see evidence for Bmp7-driven growth of the nephron postnatally. Thus, we identify a role for Bmp7 in supporting the progenitor population and driving expansion of nephrons to produce a mature kidney.

Daniel Graf

Papers

nkx3.2 mutant zebrafish accommodate the jaw joint loss through a phenocopy of the head shapes of Paleozoic agnathans

Tnf alpha and sex prevalence of oral manifestations in chronic inflammatory diseases: it's complicated

Relating multivariate shapes to genescapes using phenotype-biological process associations for craniofacial shape.

Generation and characterization of conditional alleles for bmp-2 and bmp-7

Bmp7 drives proximal tubule expansion and determines nephron number in the developing kidney.