Hot off the presses! Sep 18 Immunity

The Sep 18 issue of the Immunity is now up on Pubget (About Immunity): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Translating Inflammatory Bowel Disease Research into Clinical Medicine
  - Immunity 31(3):357-361 (2009)
  Recent studies have provided important insights into the pathogenesis of inflammatory bowel disease (IBD). The development of new therapeutic agents has been triggered by basic research and studies in mouse models of IBD. It is expected that improved translational research will lead to optimized therapy and new individualized treatment options.
• Rethinking the Pathogenesis of Asthma
  - Immunity 31(3):362-367 (2009)
  Asthma research has focused primarily on allergic pathways on the basis that the majority of asthma is associated with atopy, the recruitment of the Th2-type T cell, the cytokines, and the chemokines that are released on exposure to allergens, and the IgE pathway. However, despite considerable investment by industry, targeting these pathways has not resulted in new treatments being developed beyond blockade of cysteinyl leukotrienes and IgE and improvements in inhaled corticosteroids and β2-adrenoceptor bronchodilators. Increasingly, it is recognized that asthma is a heterogeneous disorder, and while important, allergen sensitization is only one component of the disease, with many other environmental and genetic factors playing a role. In addition, these factors act locally on a susceptible airway epithelium that is both structurally and functionally deficient. It may be worthwhile to focus on increasing the resilience of the airways to environmental insults in additi! on to improving strategies that modify adaptive immunity or suppress inflammation.
• Immune Responses to the Microbiota at the Intestinal Mucosal Surface
  - Immunity 31(3):368-376 (2009)
  The mammalian intestinal mucosal surface is continuously exposed to a complex and dynamic community of microorganisms. These microbes establish symbiotic relationships with their hosts, making important contributions to metabolism and digestive efficiency. The intestinal epithelial surface is the primary interface between the vast microbiota and internal host tissues. Given the enormous numbers of enteric bacteria and the persistent threat of opportunistic invasion, it is crucial that mammalian hosts monitor and regulate microbial interactions with intestinal epithelial surfaces. Here we discuss recent insights into how the innate and adaptive arms of the immune system collaborate to maintain homeostasis at the luminal surface of the intestinal host-microbial interface. These findings are also yielding a better understanding of how symbiotic host-microbial relationships can break down in inflammatory bowel disease.
• The Multifaceted Influence of the Mucosal Microflora on Mucosal Dendritic Cell Responses
  - Immunity 31(3):377-388 (2009)
  Over the last decade, it has become apparent that the complex interactions between components of the mucosal microflora and the mucosal immune system can involve either direct contact with dendritic cells in the lamina propria or, alternatively, contact with epithelial cells lining the mucosa that then influence the function of dendritic cells. Although in some cases these interactions involve signaling specific to particular organisms and in others, to classes of organisms, a common theme is that signaling is invariably channeled through receptors that address many organisms or all organisms such as the pattern-recognition receptors TLR and NLR. Here, I review this information with the intention of identifying how the mucosal microflora influences specific functions of the mucosal immune system such the production of particular cytokines as well as broader functions such as the maintenance of mucosal immune homeostasis and host defense.
• Intestinal Effector T Cells in Health and Disease
  - Immunity 31(3):389-400 (2009)
  Crohn's disease and ulcerative colitis are the two major forms of chronic relapsing inflammatory disorders of the human intestines collectively referred to as inflammatory bowel disease (IBD). Though a complex set of autoinflammatory disorders that can be precipitated by diverse genetic and environmental factors, a feature that appears common to IBD pathogenesis is a dysregulated effector T cell response to the commensal microbiota. Due to the heightened effector T cell activity in IBD, developmental and functional pathways that give rise to these cells are potential targets for therapeutic intervention. In this review, we highlight recent advances in our understanding of effector T cell biology in the context of intestinal immune regulation and speculate on their potential clinical significance.
• Regulatory T Cells Reinforce Intestinal Homeostasis
  - Immunity 31(3):401-411 (2009)
  Regulatory T cells help maintain intestinal homeostasis by preventing inappropriate innate and adaptive immune responses. CD4+ T cells that express Foxp3 and Tr1-like cells that produce IL-10 comprise the major regulatory populations in the intestine. CD4+Foxp3+ T cells play an important functional role in promoting tolerance of the flora and dietary proteins. Tr1-like cells can be generated in conditions that also promote effector T cell responses and may serve a similar function. In this review, we discuss the signals specific to the gastrointestinal tract that support both regulatory cell types and their distinct modes of action in the mesenteric lymph nodes and intestinal tissues. Dysregulation of intestinal immune homeostasis occurs in inflammatory bowel disease and can also be observed in graft-versus-host disease, tumor immunotherapy regimens, and acute HIV infection.
• Biology of Lung Dendritic Cells at the Origin of Asthma
  - Immunity 31(3):412-424 (2009)
  Dendritic cells (DCs) initiate and maintain adaptive T helper 2 (Th2) cell responses to inhaled allergens in asthma. Various functions like antigen uptake, migration to the draining LNs, and induction of tolerance and adaptive immunity are not equally shared by all subsets of DCs, adding considerable complexity to understanding the immunology of allergic sensitization. Whereas the epithelium was initially considered solely as a physical barrier, it is now seen as a central player in controlling the function of lung DCs through release of Th2 cell-promoting cytokines. Although DCs are sufficient and necessary for induction of Th2 cell responses to many antigens, some allergens might require antigen presentation by basophils. Clinically relevant allergens, as well as environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells, basophils, and DCs. This review summarizes t! he recent progress on our understanding how DCs control Th2 cell immunity in the lung.
• Innate Cells and T Helper 2 Cell Immunity in Airway Inflammation
  - Immunity 31(3):425-437 (2009)
  Activated mast cells, eosinophils, and basophils infiltrate the airways of asthmatics as a result of an overexuberant T helper 2 (Th2) cell immune response that drives the production of IgE, primes mast cells and basophils, and promotes tissue eosinophilia and mast cell hyperplasia. Recent evidence demonstrates that these innate effectors can be activated outside of this classical Th2 cell paradigm and that they have additional roles in promoting the development of innate and adaptive pulmonary inflammation. There is also an appreciation for the role of airway epithelial cells in orchestrating allergic pulmonary inflammation. Emerging data from basic research highlight the involvement of many unique pathways in the inflammation triggered by complex native allergens and microbes at the airway mucosal surface. Here, we review the role of effector cells and airway epithelial cells in augmenting and, at times, bypassing traditional Th2 cell-mediated allergic inflammation.
• Regulatory T Cells in Asthma
  - Immunity 31(3):438-449 (2009)
  Asthma is characterized by T helper cell 2 (Th2) type inflammation, leading to airway hyperresponsiveness and tissue remodeling. Th2 cell-driven inflammation is likely to represent an abnormal response to harmless airborne particles. These reactions are normally suppressed by regulatory T cells, which maintain airway tolerance. The anti-inflammatory cytokine IL-10 is likely to play a central role. The role of the cytokine transforming growth factor β (TGF-β) is more complex, with evidence for immune suppression and remodeling in the airways. In asthmatic individuals there is a breakdown in these regulatory mechanisms. There is emerging evidence that early life events, including exposure to allergen and infections, are critical in programming effective regulatory pathways to maintain pulmonary homeostasis. In this review we examine the clinical and experimental evidence for T regulatory cell function in the lung and discuss the events that might influence the function! ing of these cells. Ultimately, the ability to enhance regulatory function in affected individuals may represent an effective treatment for asthma.
• Establishing the Follicular Helper Identity
  - Immunity 31(3):450-452 (2009)
  Among other genes, expression of the Bcl-6 transcriptional repressor distinguishes follicular helper T (Tfh) cells from other helper T cell subsets. In this issue of Immunity, Yu et al. (2009) demonstrate that Bcl-6 directs Tfh cell differentiation.
• Diffusion and Signaling Revisited
  - Immunity 31(3):452-454 (2009)
  In this issue of Immunity, Andrews et al. (2009) used single-molecule fluorescence microscopy to demonstrate that the IgE receptor FcRI in the plasma membrane can signal in a mobile state.
• Before They Were Gut Dendritic Cells
  - Immunity 31(3):454-456 (2009)
  Gut lamina propria dendritic cell (DC) subsets have specialized functions. In this issue of Immunity, Varol et al. (2009) and Bogunovic et al. (2009) describe the different blood precursors for CD103+ and CD103− DC subsets.
• The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment
  Yu D Rao S Tsai LM Lee SK He Y Sutcliffe EL Srivastava M Linterman M Zheng L Simpson N Ellyard JI Parish IA Ma CS Li QJ Parish CR Mackay CR Vinuesa CG - Immunity 31(3):457-468 (2009)
  Follicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4+ T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Bcl-6 bound to the promoters of the Th1 and Th17 cell transcriptional regulators T-bet and RORγt and repressed IFN-γ and IL-17 production. Bcl-6 also repressed expression of many microRNAs (miRNAs) predicted to control the Tfh cell signature, including miR-17-92, which repressed CXCR5 expression. Thus, Bcl-6 positively directs Tfh cell differentiation, through combined repression of miRNAs and ! transcription factors.
• Small, Mobile FcRI Receptor Aggregates Are Signaling Competent
  - Immunity 31(3):469-479 (2009)
  Crosslinking of IgE-bound FcRI triggers mast cell degranulation. Previous fluorescence recovery after photobleaching (FRAP) and phosphorescent anisotropy studies suggested that FcRI must immobilize to signal. Here, single quantum dot (QD) tracking and hyperspectral microscopy methods were used for defining the relationship between receptor mobility and signaling. QD-IgE-FcRI aggregates of at least three receptors remained highly mobile over extended times at low concentrations of antigen that induced Syk kinase activation and near-maximal secretion. Multivalent antigen, presented as DNP-QD, also remained mobile at low doses that supported secretion. FcRI immobilization was marked at intermediate and high antigen concentrations, correlating with increases in cluster size and rates of receptor internalization. The kinase inhibitor PP2 blocked secretion without affecting immobilization or internalization. We propose that immobility is a feature of highly crosslinked immun! oreceptor aggregates and a trigger for receptor internalization, but is not required for tyrosine kinase activation leading to secretion.
• Upregulation of CD4 Expression during MHC Class II-Specific Positive Selection Is Essential for Error-free Lineage Choice
  - Immunity 31(3):480-490 (2009)
  The lineage fate of developing thymocytes is determined by the persistence or cessation of T cell receptor (TCR) signaling during positive selection, with persistent TCR signaling required for CD4 lineage choice. We show here that transcriptional upregulation of CD4 expression is essential for error-free lineage choice during major histocompatibility complex class II (MHC II)-specific positive selection and is critical for error-free lineage choice in TCR-transgenic mice whose thymocytes compete for the identical selecting ligand. CD4 upregulation occurred for endogenously encoded CD4 coreceptors, but CD4 transgenes were downregulated during positive selection, disrupting MHC II-specific TCR signaling and causing lineage errors regardless of the absolute number or signaling strength of transgenic CD4 proteins. Thus, the kinetics of CD4 coreceptor expression during MHC II-specific positive selection determines the integrity of CD4 lineage choice, revealing an elegant sy! mmetry between coreceptor kinetics and lineage choice.
• Type I Interferon Signaling in Dendritic Cells Stimulates the Development of Lymph-Node-Resident T Follicular Helper Cells
  - Immunity 31(3):491-501 (2009)
  T follicular helper (Tfh) cells represent a recently defined CD4+ T cell subset characterized by the expression of the chemokine receptor CXCR5 and an enhanced ability to support B cells to mount antibody responses. Here, we demonstrate that lymph-node-resident CXCR5+ Tfh cells and gut-homing integrin α4β7-expressing T helper cells are generated as separate subsets in the gut-draining mesenteric lymph nodes. Type I interferon signaling in dendritic cells and in nonhematopoietic cells selectively stimulates Tfh cell development in response to antigen in conjunction with Toll-like receptor (TLR)3 or TLR4 agonists. Consistent with this, the ability of dendritic cells to produce the cytokine IL-6, required for in vivo Tfh differentiation, and antibody affinity maturation are both reduced in absence of type I interferon signaling. Thus, our results identify type I interferon as a natural adjuvant that selectively supports the generation of lymph node resident Tfh cells.
• Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions
  - Immunity 31(3):502-512 (2009)
  The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103+ CX3CR1− lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b+ CD14+ CX3CR1+ lpDCs were derived from grafted Ly6Chi but not Ly6Clo monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX3CR1+ lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-α-secre! ting CX3CR1+ lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.
• Origin of the Lamina Propria Dendritic Cell Network
  - Immunity 31(3):513-525 (2009)
  CX3CR1+ and CD103+ dendritic cells (DCs) in intestinal lamina propria play a key role in mucosal immunity. However, the origin and the developmental pathways that regulate their differentiation in the lamina propria remain unclear. We showed that monocytes gave rise exclusively to CD103−CX3CR1+ lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (Flt3) ligands. In contrast, common DC progenitors (CDP) and pre-DCs, which give rise to lymphoid organ DCs but not to monocytes, differentiated exclusively into CD103+CX3CR1− lamina propria DCs under the control of Flt3 and granulocyte-macrophage-colony-stimulating factor receptor (GM-CSFR) ligands. CD103+CX3CR1− DCs but not CD103−CX3CR1+ DCs in the lamina propria constitutively expressed CCR7 and were the first DCs to transport pathogenic Salmonella from the intestinal tract to the mesenteric lymph nodes. Altogether, these results underline the! diverse origin of the lamina propria DC network and identify mucosal DCs that arise from pre-DCs as key sentinels of the gut immune system.