Immunology

Fifty Years (Well, Almost!) in Immunology [PRESIDENT'S ADDRESS]

In This Issue [IN THIS ISSUE]

Mystery Solved: IL-15 [PILLARS OF IMMUNOLOGY]

Intracellular Neutrophil Oxidants: From Laboratory Curiosity to Clinical Reality [BRIEF REVIEWS] The phagocyte NADPH oxidase is responsible for the neutrophil’s great capacity to produce reactive oxygen species (ROS). The NADPH oxidase can be assembled in the plasma membrane, as well as in membranes of intracellular vesicles, giving neutrophils the ability to direct ROS production to distinct subcellular sites. Neutrophil ROS contribute to microbial killing, trigger formation of neutrophil extracellular traps and appear to partake in inflammation control. Consequently, function-disrupting mutations in the NADPH oxidase lead to chronic granulomatous disease, characterized by severe infections and inflammatory disorders. Recent experimental data and description of a novel chronic granulomatous disease subtype (p40phox-deficiency) imply that ROS generated in intracellular compartments are key for NETosis and for controlling inflammatory signaling. We foresee boosted interest in intracellular ROS production. To fully understand where and how such ROS function, however, limitations of assay systems to measure ROS need to be appreciated, and the development of novel techniques/reagents would be highly useful.

Cutting Edge: ATM Influences Germinal Center Integrity [CUTTING EDGE] Key Points Loss of ATM leads to apoptosis of germinal center B cells. Deletion of ATM in B cells reduces germinal center frequency and size. ATM loss leads to decreased titers of class-switched Abs after immunization.

Citrullination Controls Dendritic Cell Transdifferentiation into Osteoclasts [AUTOIMMUNITY] Key Points Citrullination is the key event for DC transdifferentiation into OCs. ACPA binding to DCs can induce bone loss.

TNF and IL-1 Play Essential but Temporally Distinct Roles in Driving Cardiac Inflammation in a Murine Model of Kawasaki Disease [AUTOIMMUNITY] Kawasaki disease (KD) is a leading cause of pediatric heart disease, characterized by the emergence of life-threatening coronary vasculitis. Identifying which cytokines drive KD has been a major research goal, and both TNF and IL-1 have been identified as potential candidates. Using a murine model of KD induced by the injection of the water-soluble component of Candida albicans, we therefore undertook a mechanistic study to determine how and when these two cytokines mediate cardiac inflammation. In this study, we show that TNF signaling is active in the acute phase of cardiac inflammation, which is characterized by a diffuse myocarditis that precedes the development of coronary vasculitis. Mechanistically, TNF is produced by the myeloid cells and triggers acute cardiac inflammation by stimulating both stromal and immune compartments of the heart. In contrast to this early involvement for TNF, IL-1 signaling is dispensable for the development of acute myocarditis. Critically, although mice deficient in IL-1 signaling have extensive acute inflammation following C. albicanswater-soluble complex challenge, they do not develop coronary vasculitis. Thus, TNF and IL-1 appear to play temporally distinct roles in KD, with TNF being active in acute cardiac inflammation and IL-1 in the subsequent development of coronary vasculitis. These observations have important implications for understanding the progression of cardiac pathology in KD and the relative therapeutic use of targeting these cytokines.

Strain-Specific Manifestation of Lupus-like Systemic Autoimmunity Caused by Zap70 Mutation [AUTOIMMUNITY] A defect in TCR-proximal signaling is a major characteristic of CD4 T cells in systemic lupus erythematosus; however, it is not fully known how defects in TCR signaling lead to lupus-like systemic autoimmunity characterized by germinal center development and autoantibody production against nuclear Ags. In this study, we show that SKG mice, which develop autoimmune arthritis in a BALB/c background due to defective TCR signaling by a Zap70 mutation, develop lupus-like systemic autoimmune disease in the C57BL/6 (B6) background (B6SKG mice). B6SKG mice showed multiorgan inflammation with immune complex deposition and anti-dsDNA Ab production. Follicular helper T cells (Tfh), which help germinal center formation, were spontaneously expanded in B6SKG mice. Th cells secreting IFN- or IL-17 and regulatory T cells were also increased in B6SKG mice compared with wild-type B6 mice, with the regulatory T cell subpopulation losing the expression of CD25. Among the factors related to Tfh differentiation, the number of dendritic cells and the expression levels of the costimulatory molecules CD80, CD86, and ICOSL in dendritic cells but not in B cells were specifically increased in wild-type B6 mice compared with BALB/c mice. The inhibition of these costimulatory molecules suppressed Tfh development and lupus-like autoimmunity. Thus, a defect in TCR-proximal signaling leads to lupus-like systemic autoimmunity under the specific genetic background that facilitates Tfh development.

A New IRF-1-Driven Apoptotic Pathway Triggered by IL-4/IL-13 Kills Neonatal Th1 Cells and Weakens Protection against Viral Infection [IMMUNE REGULATION] Early life immune responses are deficient in Th1 lymphocytes that compromise neonatal vaccination. We found that IL-4 and IL-13 engage a developmentally expressed IL-4Rα/IL-13Rα1 heteroreceptor to endow IFN regulatory factor 1 (IRF-1) with apoptotic functions, which redirect murine neonatal Th1 reactivation to cell death. IL-4/IL-13–induced STAT6 phosphorylation serves to enhance IRF-1 transcription and promotes its egress from the nucleus. In the cytoplasm, IRF-1 can no longer serve as an anti-viral transcription factor but, instead, colocalizes with Bim and instigates the mitochondrial, or intrinsic, death pathway. The new pivotal function of IRF-1 in the death of neonatal Th1 cells stems from the ability of its gene to bind STAT6 for enhanced transcription and the proficiency of its protein to precipitate Bim-driven apoptosis. This cytokine-induced, IRF-1–mediated developmental death network weakens neonatal Th1 responses during early life vaccination and increases susceptibility to viral infection.

Dlg1 Maintains Dendritic Cell Function by Securing Voltage-Gated K+ Channel Integrity [IMMUNE REGULATION] Key Points Dlg1-deficient DCs possess a lower capacity to mediate Ab responses. Dlg1 deficiency in DCs impairs Ag update and cytokine production. Dlg1 modulates DC activation and function through voltage-gated K+ channels.

Correction: CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses [CORRECTIONS]

Evidence of Trained Immunity in a Fish: Conserved Features in Carp Macrophages [INNATE IMMUNITY AND INFLAMMATION] Key points Carp macrophages exhibit a trained immunity-like profile in vitro. Both peptidoglycan and β-glucan can induce trained immunity in carp macrophages.

USP19 Inhibits TNF-{alpha}- and IL-1{beta}-Triggered NF-{kappa}B Activation by Deubiquitinating TAK1 [INNATE IMMUNITY AND INFLAMMATION] Key Points USP19 negatively regulates TAK1-mediated NF-B activation. Usp19 deficiency promotes TNF-α– and IL-1β–induced inflammatory response. USP19 removes K63- and K27-linked polyubiquitin chains from TAK1.

HB-EGF Synthesized by CD4 T Cells Modulates Allergic Airway Eosinophilia by Regulating IL-5 Synthesis [ALLERGY AND OTHER HYPERSENSITIVITIES] Key Points Intracellular HB-EGF expressed by CD4 T cells increases IL-5 expression by TH2 cells. HB-EGF in CD4 T cells regulates IL-5 synthesis by inhibiting Bcl-6.

The Lysophosphatidylcholine Transporter MFSD2A Is Essential for CD8+ Memory T Cell Maintenance and Secondary Response to Infection [IMMUNE REGULATION] Key Points MFSD2A is required for CD8+ memory T cell maintenance. MFSD2A deficiency results in defective import of LPC species into CD8+ T cells. Import of LPC helps to maintain memory T cell homeostasis.

Regulation of Diabetogenic Immunity by IL15-Activated Regulatory CD8 T Cells in Type 1 Diabetes [IMMUNE REGULATION] Key Points NOD mice are deficient in number and function of CD8 Tregs that control the germinal center. Treatment with IL-15 superagonist expands NOD CD8 Tregs and restores their activity. IL-15–activated CD8 Tregs delay the adoptive transfer of type 1 diabetes.

Macrophages Guard Endothelial Lineage by Hindering Endothelial-to-Mesenchymal Transition: Implications for the Pathogenesis of Systemic Sclerosis [INNATE IMMUNITY AND INFLAMMATION] Key points Lung endothelial precursor cells are committed to EndoMT during experimental fibrosis. Signals in the sera of patients with systemic sclerosis reproduce EndoMT in vitro. Macrophages protect from both EndoMT induction and experimental fibrosis.

C-Reactive Protein Promotes Inflammation through Fc{gamma}R-Induced Glycolytic Reprogramming of Human Macrophages [INNATE IMMUNITY AND INFLAMMATION] Key Points Under inflammatory conditions, CRP is not only a marker but also a driver of inflammation by human macrophages. CRP enhances inflammatory cytokine production via FcR-induced metabolic reprogramming through kinases Syk, PI3K, and AKT2.

The Cross-Talk between miR-511-3p and C-Type Lectin Receptors on Dendritic Cells Affects Dendritic Cell Function [IMMUNE REGULATION] Key Points The miR-511-3p regulates MR and DC-SIGN expression in human DCs. Silencing miR-511-3p expression promotes anti-inflammatory DC phenotype. Changes in miR-511-3p levels in DCs affect T cell polarization in DC–T coculture.

Inflammasome-Independent and Atypical Processing of IL-1{beta} Contributes to Acid Aspiration-Induced Acute Lung Injury [INNATE IMMUNITY AND INFLAMMATION] Key Points: Inflammasome-independent IL-1β production contributes to aspiration pneumonitis. Acidic stress induces the production of mature IL-1β in macrophages. A novel cleavage site of IL-1β in response to acidic stress was identified.