Latest Articles Include:
- Host Defense Pathways: Role of Redundancy and Compensation in Infectious Disease Phenotypes
- Immunity 34(5):629-636 (2011)
Innate host defense pathways consist of microbial sensors, their signaling pathways, and the antimicrobial effector mechanisms. Several classes of host defense pathways are currently known, each comprising several pattern-recognition receptors that detect different types of pathogens. These pathways interact with one another in a variety of ways that can be categorized into cooperation, complementation, and compensation. Understanding the principles of these interactions is important for better understanding of host defense mechanisms, as well as for correct interpretation of immunodeficient phenotypes.
- Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity
- Immunity 34(5):637-650 (2011)
Toll-like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to microbial pathogens. TLR-mediated recognition of components derived from a wide range of pathogens and their role in the subsequent initiation of innate immune responses is widely accepted; however, the recent discovery of non-TLR PRRs, such as C-type lectin receptors, NOD-like receptors, and RIG-I-like receptors, suggests that many aspects of innate immunity are more sophisticated and complex. In this review, we will focus on the role played by TLRs in mounting protective immune responses against infection and their crosstalk with other PRRs with respect to pathogen recognition.
- Myeloid C-type Lectin Receptors in Pathogen Recognition and Host Defense
- Immunity 34(5):651-664 (2011)
C-type lectin receptors (CLRs) comprise a heterogeneous group of transmembrane proteins. Many of them are expressed in myeloid cells and signal in response to pathogen-derived or self ligands to initiate or regulate cell activation. Here, we review the properties of myeloid CLRs, highlighting how their signaling function is coordinated with that of other innate receptor families to control immunity to infection.
- Regulation of the Antimicrobial Response by NLR Proteins
- Immunity 34(5):665-679 (2011)
Nucleotide-binding, oligomerization domain (NOD)-like receptor (NLR) proteins are a family of innate immune receptors that play a pivotal role in microbial sensing, leading to the initiation of antimicrobial immune responses. Dysregulation of the function of multiple NLR family members has been linked, both in mice and humans, to a propensity for infection and autoinflammatory disease. Despite our increased understanding of NLR function and interactions, many aspects related to mechanisms of sensing, downstream signaling, and in vivo functions remain elusive. In this review, we focus on key members of the NLR family, describing their activation by diverse microbes, downstream effector functions, and interactions with each other and with other innate sensor protein families. Also discussed is the role of microbial sensing by NLR receptors leading to activation of the adaptive immune arm that collaborates in the antimicrobial defense.
- Immune Signaling by RIG-I-like Receptors
- Immunity 34(5):680-692 (2011)
The RIG-I-like receptors (RLRs) RIG-I, MDA5, and LGP2 play a major role in pathogen sensing of RNA virus infection to initiate and modulate antiviral immunity. The RLRs detect viral RNA ligands or processed self RNA in the cytoplasm to trigger innate immunity and inflammation and to impart gene expression that serves to control infection. Importantly, RLRs cooperate in signaling crosstalk networks with Toll-like receptors and other factors to impart innate immunity and to modulate the adaptive immune response. RLR regulation occurs at a variety of levels ranging from autoregulation to ligand and cofactor interactions and posttranslational modifications. Abberant RLR signaling or dysregulation of RLR expression is now implicated in the development of autoimmune diseases. Understanding the processes of RLR signaling and response will provide insights to guide RLR-targeted therapeutics for antiviral and immune-modifying applications.
- Gut Nod2 Calls the Bone Marrow for Monocyte Reinforcements
- Immunity 34(5):693-695 (2011)
Nod2 is an intracellular sensor linked to Crohn's disease, an inflammatory malady of the intestinal tract. In this issue of Immunity, Kim et al. (2011) demonstrate that Nod2 is responsible for regulating monocyte-attracting chemokines to the inflamed gut.
- A New Twist on the PYRIN Mediterranean Coast
- Immunity 34(5):695-697 (2011)
Familial Mediterranean fever is caused by mutations of the PYRIN protein. Chae et al. (2011) provide evidence for a ASC protein-dependent pathway of caspase-1 activation in which gain-of-function PYRIN mutations lead to IL-1β cytokine overproduction and inflammatory disease.
- A Narrow Circle of Mutual Friends
- Immunity 34(5):697-699 (2011)
Commensal microbiota confers a goldilocks state of alertness to pathogens, yet restrains deleterious inflammation. In this issue of Immunity, Geuking et al. (2011) demonstrate that a minimal bacterial community of the Schaedler flora establishes a balance between pro- and anti-inflammatory T cells in the gut.
- Chronic Infections Capture Little Attention of the Masses
- Immunity 34(5):699-701 (2011)
In this issue of Immunity, Egen et al. (2011) provide compelling evidence that only a minute fraction of mycobacteria-specific T cells present in a granuloma are actively fulfilling effector functions, an observation that may in fact be a general feature of chronic infections.
- The Calcium Sensors STIM1 and STIM2 Control B Cell Regulatory Function through Interleukin-10 Production
- Immunity 34(5):703-714 (2011)
A chief Ca2+ entry pathway in immune cells is store-operated Ca2+ (SOC) influx, which is triggered by depletion of Ca2+ from the endoplasmic reticulum (ER). However, its physiological role in B cells remains elusive. Here, we show that ER calcium sensors STIM1- and STIM2-induced SOC influx is critical for B cell regulatory function. B cell-specific deletion of STIM1 and STIM2 in mice caused a profound defect in B cell receptor (BCR)-induced SOC influx and proliferation. However, B cell development and antibody responses were unaffected. Remarkably, B cells lacking both STIM proteins failed to produce the anti-inflammatory cytokine IL-10 because of defective activation of nuclear factor of activated T cells (NFAT) after BCR stimulation. This resulted in exacerbation of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our data establish STIM-dependent SOC influx as a key signal for B cell regulatory function required to limit autoimmunity.
- The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock
- Immunity 34(5):715-728 (2011)
Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
- B7-H2 Is a Costimulatory Ligand for CD28 in Human
- Immunity 34(5):729-740 (2011)
CD28 and CTLA-4 are cell surface cosignaling molecules essential for the control of T cell activation upon the engagement of their ligands B7-1 and B7-2 from antigen-presenting cells. By employing a receptor array assay, we have demonstrated that B7-H2, best known as the ligand of inducible costimulator, was a ligand for CD28 and CTLA-4 in human, whereas these interactions were not conserved in mouse. B7-H2 and B7-1 or B7-2 interacted with CD28 through distinctive domains. B7-H2-CD28 interaction was essential for the costimulation of human T cells' primary responses to allogeneic antigens and memory recall responses. Similar to B7-1 and B7-2, B7-H2 costimulation via CD28 induced survival factor Bcl-xL, downregulated cell cycle inhibitor p27kip1, and triggered signaling cascade of ERK and AKT kinase-dependent pathways. Our findings warrant re-evaluation of CD28 and CTLA-4's functions previously attributed exclusively to B7-1 and B7-2 and have important implications in th erapeutic interventions against human diseases.
- Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin
- Immunity 34(5):741-754 (2011)
Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is a n important mechanism for Smad-independent Th17 cell differentiation.
- Gain-of-Function Pyrin Mutations Induce NLRP3 Protein-Independent Interleukin-1β Activation and Severe Autoinflammation in Mice
- Immunity 34(5):755-768 (2011)
Missense mutations in the C-terminal B30.2 domain of pyrin cause familial Mediterranean fever (FMF), the most common Mendelian autoinflammatory disease. However, it remains controversial as to whether FMF is due to the loss of an inhibitor of inflammation or to the activity of a proinflammatory molecule. We generated both pyrin-deficient mice and "knockin" mice harboring mutant human B30.2 domains. Homozygous knockin, but not pyrin-deficient, mice exhibited spontaneous bone marrow-dependent inflammation similar to but more severe than human FMF. Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients. The inflammatory phenotype of knockin mice was completely ablated by crossing with IL-1 receptor-deficient or adaptor molecule ASC-deficient mice, but not NLRP3-deficient mice. Thus, our data provide evidence for an ASC-dependent NLRP3-independent inflammasome in which gain-of-function pyrin mutations cause autoinflammatory disease.
- The Nod2 Sensor Promotes Intestinal Pathogen Eradication via the Chemokine CCL2-Dependent Recruitment of Inflammatory Monocytes
- Immunity 34(5):769-780 (2011)
The intracellular sensor Nod2 is activated in response to bacteria, and the impairment of this response is linked to Crohn's disease. However, the function of Nod2 in host defense remains poorly understood. We found that Nod2−/− mice exhibited impaired intestinal clearance of Citrobacter rodentium, an enteric bacterium that models human infection by pathogenic Escherichia coli. The increased bacterial burden was preceded by reduced CCL2 chemokine production, inflammatory monocyte recruitment, and Th1 cell responses in the intestine. Colonic stromal cells, but not epithelial cells or resident CD11b+ phagocytic cells, produced CCL2 in response to C. rodentium in a Nod2-dependent manner. Unlike resident phagocytic cells, inflammatory monocytes produced IL-12, a cytokine that induces adaptive immunity required for pathogen clearance. Adoptive transfer of Ly6Chi monocytes restored the clearance of the pathogen in infected Ccr2−/− mice. Thus, Nod2 mediates CCL2-CCR2-d ependent recruitment of inflammatory monocytes, which is important in promoting bacterial eradication in the intestine.
- Protective Capacity of Memory CD8+ T Cells Is Dictated by Antigen Exposure History and Nature of the Infection
- Immunity 34(5):781-793 (2011)
Infection or vaccination confers heightened resistance to pathogen rechallenge because of quantitative and qualitative differences between naive and primary memory T cells. Herein, we show that secondary (boosted) memory CD8+ T cells were better than primary memory CD8+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8+ T cells within lymph nodes, which is reduced by antigen restimulation, was critical for both viral control in lymph nodes and for the sustained CD8+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen stimulation shapes memory CD8+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases.
- Intestinal Bacterial Colonization Induces Mutualistic Regulatory T Cell Responses
- Immunity 34(5):794-806 (2011)
Mammals harbor a dense commensal microbiota in the colon. Regulatory T (Treg) cells are known to limit microbe-triggered intestinal inflammation and the CD4+ T cell compartment is shaped by the presence of particular microbes or bacterial compounds. It is, however, difficult to distinguish whether these effects reflect true mutualistic immune adaptation to intestinal colonization or rather idiosyncratic immune responses. To investigate truly mutualistic CD4+ T cell adaptation, we used the altered Schaedler flora (ASF). Intestinal colonization resulted in activation and de novo generation of colonic Treg cells. Failure to activate Treg cells resulted in the induction of T helper 17 (Th17) and Th1 cell responses, which was reversed by wild-type Treg cells. Efficient Treg cell induction was also required to maintain intestinal homeostasis upon dextran sulfate sodium-mediated damage in the colon. Thus, microbiota colonization-induced Treg cell responses are a fundamental in trinsic mechanism to induce and maintain host-intestinal microbial T cell mutualism.
- Intravital Imaging Reveals Limited Antigen Presentation and T Cell Effector Function in Mycobacterial Granulomas
- Immunity 34(5):807-819 (2011)
Cell-mediated adaptive immunity is critical for host defense, but little is known about T cell behavior during delivery of effector function. Here we investigate relationships among antigen presentation, T cell motility, and local production of effector cytokines by CD4+ T cells within hepatic granulomas triggered by Bacille Calmette-Guérin or Mycobacterium tuberculosis. At steady-state, only small fractions of mycobacteria-specific T cells showed antigen-induced migration arrest within granulomas, resulting in low-level, polarized secretion of cytokines. However, exogenous antigen elicited rapid arrest and robust cytokine production by the vast majority of effector T cells. These findings suggest that limited antigen presentation and/or recognition within granulomas evoke a muted T cell response drawing on only a fraction of the host's potential effector capacity. Our results provide new insights into the regulation of host-protective functions, especially how antigen availability influences T cell dynamics and, in turn, effector T cell function during chronic infection.
- Endothelial Heparan Sulfate Controls Chemokine Presentation in Recruitment of Lymphocytes and Dendritic Cells to Lymph Nodes
- Immunity 34(5):820 (2011)