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1.  Respiratory epithelial cells orchestrate pulmonary innate immunity 
Nature immunology  2014;16(1):27-35.
The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and ‘instruct’ the professional immune system to protect the lungs from infection and injury.
doi:10.1038/ni.3045
PMCID: PMC4318521  PMID: 25521682
2.  [No title available] 
PMCID: PMC4106986  PMID: 24952503
3.  [No title available] 
PMCID: PMC4110708  PMID: 24973821
4.  ASC has extracellular and prionoid activities that propagate inflammation 
Nature immunology  2014;15(8):727-737.
Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adapter ASC and assembly of an ASC speck. ASC specks recruit and activate caspase-1, which induces IL-1β cytokine maturation and pyroptotic cell death. Here we show that after pyroptosis ASC specks accumulate in the extracellular space, where they promote further IL-1β maturation. In addition, phagocytosis of ASC specks induces lysosomal damage, nucleation of soluble ASC as well as caspase-1 and IL-1β activation in the recipient cell. ASC specks appear in bodily fluids from inflamed tissues and autoantibodies against ASC specks develop in patients and animals with autoimmune pathologies. Together, these findings reveal extracellular functions of ASC specks and a novel form of cell-to-cell communication.
doi:10.1038/ni.2913
PMCID: PMC4116676  PMID: 24952505
5.  Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility 
Nature immunology  2014;15(8):777-788.
A characteristic feature of asthma is the aberrant accumulation, differentiation or function of memory CD4+ T cells that produce type 2 cytokines (TH2 cells). By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, we identified enhancers with known and potential roles in the normal differentiation of human TH1 cells and TH2 cells. We discovered disease-specific enhancers in T cells that differ between healthy and asthmatic individuals. Enhancers that gained the histone H3 Lys4 dimethyl (H3K4me2) mark during TH2 cell development showed the highest enrichment for asthma-associated single nucleotide polymorphisms (SNPs), which supported a pathogenic role for TH2 cells in asthma. In silico analysis of cell-specific enhancers revealed transcription factors, microRNAs and genes potentially linked to human TH2 cell differentiation. Our results establish the feasibility and utility of enhancer profiling in well-defined populations of specialized cell types involved in disease pathogenesis.
doi:10.1038/ni.2937
PMCID: PMC4140783  PMID: 24997565
6.  Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1β production 
Nature immunology  2014;15(6):538-545.
Double-stranded DNA (dsDNA) in the cytoplasm triggers interleukin-1β (IL-1β) production as an anti-viral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune adapter CARD9. Dendritic cell transfection with dsDNA or infection with a DNA virus induces the formation of dsDNA-Rad50-CARD9 signaling complexes for NF-κB activation and pro-IL-1β generation. Primary cells conditionally deficient for Rad50 or lacking CARD9 consequently exhibit defective DNA-induced IL-1β production, and Card9−/− mice have impaired inflammatory responses upon DNA virus infection in vivo. These results define a cytosolic DNA recognition pathway for inflammation and a physical and functional connection between a conserved DNA-damage sensor and the innate immune response to pathogens.
doi:10.1038/ni.2888
PMCID: PMC4309842  PMID: 24777530
7.  [No title available] 
PMCID: PMC4289613  PMID: 24859451
8.  Cutaneous immuno-surveillance and regulation of inflammation by group 2 innate lymphoid cells 
Nature immunology  2013;14(6):564-573.
Type 2 immunity is critical for defense against cutaneous infections, but also underlies the development of allergic skin diseases. We report the identification in normal murine dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depends on interleukin 7 (IL-7) and constitutively produces IL-13. Intravital multiphoton microscopy revealed that dermal ILC2 specifically interact with mast cells, whose function was suppressed by IL-13. Treatment of Rag1−/− mice with IL-2 resulted in the expansion of activated, IL-5-producing dermal ILC2, leading to spontaneous dermatitis characterized by eosinophil infiltrate and activated mast cells. Our data show that ILC2 exhibit both pro- and anti-inflammatory properties and uncover a novel interactive pathway between two innate immune cell populations implicated in type 2 immunity and allergic diseases.
doi:10.1038/ni.2584
PMCID: PMC4282745  PMID: 23603794
9.  Quantitative and Temporal Requirements Revealed for Zap-70 Catalytic Activity During T Cell Development 
Nature immunology  2014;15(7):687-694.
The catalytic activity of Zap-70 is crucial for T cell receptor (TCR) signaling, but the quantitative and temporal requirements for its function in thymocyte development are not known. Using a chemical-genetic system to selectively and reversibly inhibit Zap-70 catalytic activity in a model of synchronized thymic selection, we showed that CD4+CD8+ thymocytes integrate multiple, transient, Zap-70-dependent signals over more than 36 h to reach a cumulative threshold for positive selection, whereas one hour of signaling was sufficient for negative selection. Titration of Zap-70 activity resulted in graded reductions in positive and negative selection but did not decrease the cumulative TCR signals integrated by positively selected OT-I cells, revealing heterogeneity, even among CD4+CD8+ thymocytes expressing identical TCRs undergoing positive selection.
doi:10.1038/ni.2918
PMCID: PMC4095875  PMID: 24908390
10.  TCF-1 and LEF-1 act upstream of Th-POK to promote CD4+ T cell lineage choice and cooperate with Runx3 to silence the Cd4 gene in CD8+ T cells 
Nature immunology  2014;15(7):646-656.
TCF-1 and LEF-1 are essential for early T cell development, but their roles beyond the CD4+CD8+ double positive (DP) stage are unknown. By specific ablation in DP thymocytes, we demonstrated that deficiency in TCF-1 and LEF-1 diminished CD4+ T cell output and redirected CD4+ T cells to a CD8+ T cell fate. The role of TCF-1 and LEF-1 in CD4-CD8 lineage choice was partly mediated by direct positive regulation of Th-POK. Furthermore, loss of TCF-1 and LEF-1 unexpectedly caused CD4 derepression in CD8+ lineage-committed T cells without affecting the expression of Runx factors. Instead, TCF-1 physically interacted with Runx3 to cooperatively silence the Cd4 gene. Thus, TCF-1 and LEF-1 adopt distinct genetic wiring to program CD4+ fate decision and establish CD8+ T cell identity.
doi:10.1038/ni.2897
PMCID: PMC4064003  PMID: 24836425
11.  CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype 
Nature immunology  2014;15(7):631-637.
Memory B cells (MBCs) are long-lived sources of rapid, isotype-switched secondary antibody-forming cell (AFC) responses. Whether MBCs homogeneously retain the ability to self-renew and terminally differentiate or if these functions are compartmentalized into MBC subsets has been unclear. It was previously suggested that antibody isotype controls MBC differentiation upon restimulation. Here we demonstrate that subdividing MBCs based on expression of CD80 and PD-L2, independent of isotype, identified MBC subsets with distinct functional behaviors upon rechallenge. CD80+PD-L2+ MBCs differentiated rapidly into AFCs but did not generate germinal centers (GCs); conversely CD80−PD-L2− MBCs generated few early AFCs but robustly seeded GCs. Gene expression patterns of subsets support both the identity and function of these distinct MBC types. Hence, MBC differentiation and regeneration are compartmentalized.
doi:10.1038/ni.2914
PMCID: PMC4105703  PMID: 24880458
12.  The AGC kinase serum- and glucocorticoid-regulated kinase 1 (SGK1) regulates TH1 and TH2 differentiation downstream of mTORC2 
Nature immunology  2014;15(5):457-464.
Serum- and glucocorticoid-regulated kinase 1 (SGK1) is an AGC kinase that regulates membrane sodium channel expression in renal tubular cells in an mTORC2-dependent manner. We hypothesized that SGK1 might represent a novel mTORC2-dependent regulator of T cell differentiation and function. Here we demonstrate that upon activation by mTORC2, SGK1 promoted TH2 differentiation by negatively regulating the NEDD4-2 E3 ligase-mediated destruction of transcription factor JunB. Simultaneously, SGK1 repressed the production of interferon-γ (IFN-γ) by controlling the expression of the long isoform of transcription factor TCF-1. Consistent with these findings, mice with a selective deletion of SGK1 in T cells were resistant to experimentally induced asthma, generated robust amounts of IFN-γ in response to viral infections and more readily rejected tumors.
doi:10.1038/ni.2867
PMCID: PMC4267697  PMID: 24705297
13.  USP15 stabilizes MDM2 to mediate cancer cell survival and inhibit antitumor T cell responses 
Nature immunology  2014;15(6):562-570.
Deubiquitinases (DUBs) represent a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized an E3 ubiquitin ligase, MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses.
doi:10.1038/ni.2885
PMCID: PMC4032322  PMID: 24777531
Deubiquitinase; USP15; MDM2; T-cell activation; tumorigenesis
14.  Inflammation-induced repression of Foxp3-bound chromatin in regulatory T cells 
Nature immunology  2014;15(6):580-587.
The transcription factor Foxp3 is indispensable for the ability of regulatory T (Treg) cells to suppress fatal inflammation. Here, we characterized the role of Foxp3 in chromatin remodeling and regulation of gene expression in actively suppressing Treg cells in an inflammatory setting. Although genome-wide Foxp3 occupancy of DNA regulatory elements was similar in resting and in vivo activated Treg cells, Foxp3-bound enhancers were poised for repression only in activated Treg cells. Following activation, Foxp3-bound sites showed reduced chromatin accessibility and selective H3K27 tri-methylation, which was associated with Ezh2 recruitment and downregulation of nearby gene expression. Thus, Foxp3 poises its targets for repression by facilitating formation of repressive chromatin in regulatory T cells upon their activation in response to inflammatory cues.
doi:10.1038/ni.2868
PMCID: PMC4112080  PMID: 24728351
15.  RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells 
Nature immunology  2008;10(1):83-91.
The mucosal immune system of the intestine is separated from a vast array of microbes by a single layer of epithelial cells. Cues from the commensal microflora are needed to maintain epithelial homeostasis, but the molecular and cellular identities of these cues are unclear. Here we provide evidence that signals from the commensal microflora contribute to the differentiation of a lymphocyte population coexpressing stimulatory natural killer cell receptors and the transcription factor RORγt that produced interleukin 22 (IL-22). The emergence of these IL-22-producing RORγthiNKp46+NK1.1int cells depended on RORγt expression, which indicated that these cells may have been derived from lymphoid tissue–inducer cells. IL-22 released by these cells promoted the production of antimicrobial molecules important in the maintenance of mucosal homeostasis.
doi:10.1038/ni.1684
PMCID: PMC4217274  PMID: 19029903
16.  Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation 
Nature immunology  2014;15(5):473-481.
Regulatory T (Treg) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic Treg development is undefined. We demonstrate that Treg progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced Treg development. Conversely, TNFRSF agonists enhanced Treg differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the Treg repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated Treg development. Thus TNFRSF expression on Treg progenitors translates strong TCR signals into molecular parameters that specifically promote Treg differentiation and shape the Treg repertoire.
doi:10.1038/ni.2849
PMCID: PMC4000541  PMID: 24633226
17.  Protein Kinase C-η Controls CTLA-4-Mediated Regulatory T Cell Function 
Nature immunology  2014;15(5):465-472.
Regulatory T cells (Treg cells), which maintain immune homeostasis and self-tolerance, form an immunological synapse (IS) with antigen-presenting cells (APCs). However, signaling events at the Treg IS remain unknown. Here we show that protein kinase C-η (PKC-η) associated with CTLA-4 and was recruited to the Treg IS. PKC-η-deficient Treg cells displayed defective suppressive activity, including suppression of tumor immunity but not autoimmune colitis. Phosphoproteomic analysis revealed an association between CTLA-4-PKC-η and the GIT-PIX-PAK complex, an IS-localized focal adhesion complex. Defective activation of this complex in PKC-η-deficient Treg cells was associated with reduced CD86 depletion from APCs by Treg cells. These results reveal a novel CTLA-4-PKC-η signaling axis required for contact-dependent suppression, implicating this pathway as a potential cancer immunotherapy target.
doi:10.1038/ni.2866
PMCID: PMC4040250  PMID: 24705298
18.  The enemy within: endogenous retroelements and autoimmune disease 
Nature immunology  2014;15(5):415-422.
Inappropriate or chronic detection of self nucleic acids by the innate immune system underlies a number of human autoimmune diseases. We discuss here an unexpected source of endogenous immunostimulatory nucleic acids: the reverse transcribed cDNAs of endogenous retroelements. The interplay between innate immune sensing and clearance of retroelement cDNAs has important implications for understanding immune responses to infectious retroviruses like human immunodeficiency virus (HIV). Further, cDNA detection by the innate immune system reveals an evolutionary tradeoff: selection for a vigorous, sensitive response to infectious retroviruses may predispose to inappropriate detection of endogenous retroelements. We propose that this tradeoff has placed unique constraints on the sensitivity of the DNA-activated antiviral response, with implications for the interactions of DNA viruses and retroviruses with their hosts. Finally, we discuss how a better understanding of the intersection of retroelement biology and innate immunity can guide the way to novel therapies for specific autoimmune diseases.
doi:10.1038/ni.2872
PMCID: PMC4131434  PMID: 24747712
19.  Interleukin-6 signaling promotes alternative macrophage activation to limit obesity-associated insulin resistance and endotoxemia 
Nature immunology  2014;15(5):423-430.
Obesity and insulin resistance are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation, however its role in this context remains controversial. Here, we show that mice with inactivated Il6ra gene in myeloid cells (Il6raΔmyel) displayed exaggerated deterioration of glucose homeostasis upon diet-induced obesity due to enhanced insulin resistance. Insulin target tissues showed increased inflammation and a shift in macrophage polarization. IL-6 induced IL-4-receptor expression and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6raΔmyel mice were resistant to IL-4-mediated alternative macrophage polarization and exhibited increased susceptibility to LPS-induced endotoxemia. These results reveal IL-6 signaling as an important determinant for alternative macrophage-activation and assign IL-6 an unexpected homeostatic role to limit inflammation.
doi:10.1038/ni.2865
PMCID: PMC4161471  PMID: 24681566
20.  ORIGINS OF CD4+ EFFECTOR AND CENTRAL MEMORY T CELLS 
Nature immunology  2011;12(6):467-471.
Lineage-committed effector CD4+ T cells are generated at the peak of the primary response and are followed by heterogeneous populations of central and effector memory cells. Here we review the evidence that Th1 effector cells survive the contraction phase of the primary response and become effector memory cells. We discuss the applicability of this concept to the Th2, Th17, follicular helper cell, and induced regulatory T cell lineages. We also discuss how central memory cells are formed with an emphasis on the role that B cells play in this process.
PMCID: PMC4212218  PMID: 21739668
21.  Dominant-Activating, Germline Mutations in Phosphoinositide 3-Kinase p110δ Cause T Cell Senescence and Human Immunodeficiency 
Nature immunology  2013;15(1):88-97.
The p110δ subunit of phosphoinositide 3-kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report three different germline, heterozygous, gain-of-function mutations in the PIK3CD gene encoding p110δ in fourteen patients from seven families. These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and CMV and/or EBV viremia. Strikingly, naïve and central memory T cells were severely deficient, while senescent effector T cells were over-represented. In vitro, patient T cells exhibited increased phosphorylation of Akt and hyperactivation of mTOR, enhanced glucose uptake and terminal effector differentiation. Importantly, treatment with rapamycin to inhibit mTOR activity in vivo partially restored naïve T cells, largely rescued the in vitro T cell defects, and improved clinical course.
doi:10.1038/ni.2771
PMCID: PMC4209962  PMID: 24165795
22.  Fishing for mammalian paradigms in the teleost immune system 
Nature immunology  2013;14(4):320-326.
Recent years have witnessed a renaissance in the study of fish immune systems. Such studies have greatly expanded the knowledge of the evolution and diversification of vertebrate immune systems. Several findings in those studies have overturned old paradigms about the immune system and led to the discovery of novel aspects of mammalian immunity. Here I focus on how findings pertaining to immunity in teleost (bony) fish have led to major new insights about mammalian B cell function in innate and adaptive immunity. Additionally, I illustrate how the discovery of the most ancient mucosal immunoglobulin described thus far will help resolve unsettled paradigms of mammalian mucosal immunity.
doi:10.1038/ni.2549
PMCID: PMC4203445  PMID: 23507645
23.  Fingerprinting Ikaros 
Nature immunology  2013;14(10):1034-1035.
Zinc fingers 1 and 4 of Ikaros have unique functions in the selection of Ikaros target genes, lymphocyte development and the suppression of leukemogenesis.
doi:10.1038/ni.2709
PMCID: PMC4197131  PMID: 24048134
24.  Understanding immune senescence to improve vaccine responses 
Nature immunology  2013;14(5):428-436.
In the older adult the benefits of vaccination to prevent infectious disease are limited, mainly due to the adaptive immune system’s inability to generate protective immunity. Age-dependent decline in immune competence, often referred to as immunosenescence, results from progressive deterioration of innate and adaptive immune responses and most of the insights into mechanisms of immune aging have derived from studies in murine models. In this Review, we explore how well these models are applicable to understand the aging process throughout the 80–100 years of human life and discuss recent advances in uncovering and characterizing the mechanisms underlying age-associated defective adaptive immunity in humans.
doi:10.1038/ni.2588
PMCID: PMC4183346  PMID: 23598398
25.  IFNL3 (IL28B) favorable genotype escapes hepatitis C virus-induced microRNAs and mRNA decay 
Nature immunology  2013;15(1):72-79.
The IFNL3 (IL28B) gene has received immense attention in the hepatitis C virus (HCV) field as multiple independent genome-wide association studies identified a strong association between polymorphisms near the IFNL3 gene and HCV clearance. However, the mechanism underlying this association has remained elusive. In this study, we report the identification of a functional polymorphism (rs4803217) located in the 3′ untranslated region (3′ UTR) of the IFNL3 mRNA that dictates transcript stability. This polymorphism influences AU-rich element-mediated decay as well as the binding of HCV-induced microRNAs during infection. Together, these pathways mediate robust repression of the unfavorable IFNL3 genotype. These data reveal a novel mechanism by which HCV attenuates the antiviral response and uncover new potential therapeutic targets for HCV treatment.
doi:10.1038/ni.2758
PMCID: PMC4183367  PMID: 24241692

Results 1-25 (593)