Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that ...deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon-γ (IFN-γ) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology.
Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While ...the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian beta-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections.
Mutations that impact immune cell migration and result in immune deficiency illustrate the importance of cell movement in host defense. In humans, loss-of-function mutations in DOCK8, a guanine ...exchange factor involved in hematopoietic cell migration, lead to immunodeficiency and, paradoxically, allergic disease. Here, we demonstrate that, like humans, Dock8
mice have a profound type 2 CD4
helper T (T
2) cell bias upon pulmonary infection with Cryptococcus neoformans and other non-T
2 stimuli. We found that recruited Dock8
CX3CR1
mononuclear phagocytes are exquisitely sensitive to migration-induced cell shattering, releasing interleukin (IL)-1β that drives granulocyte-macrophage colony-stimulating factor (GM-CSF) production by CD4
T cells. Blocking IL-1β, GM-CSF or caspase activation eliminated the type-2 skew in mice lacking Dock8. Notably, treatment of infected wild-type mice with apoptotic cells significantly increased GM-CSF production and T
2 cell differentiation. This reveals an important role for cell death in driving type 2 signals during infection, which may have implications for understanding the etiology of type 2 CD4
T cell responses in allergic disease.
T follicular helper (Tfh) cells are a CD4+ T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells ...expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection. Furthermore, we demonstrated that expression of Talin-1, an adaptor protein that regulates LFA-1 affinity, dictated Tfh versus Th2 effector cell differentiation. Collectively, our results define unique functions for LFA-1 in the Tfh cell effector program and suggest that integrin activity is important in lineage decision-making events in the adaptive immune system.
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•Mouse and human Tfh cells have high expression of LFA-1•Survival of Tfh cells during the germinal center reaction requires LFA-1•LFA-1 is required for Tfh cell development and immunity to helminth infection•Tfh cell differentiation selectively requires Talin-1-dependent integrin activation
T follicular helper cell differentiation is required for germinal center formation and long-lived humoral immunity. Meli et al. report that a high-affinity form of the integrin LFA-1 regulates both the development and maintenance of this T cell subset and is critical for generation of protective humoral immunity to intestinal helminth infection.
Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T ...cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.
The human microbiota is composed of diverse forms of microorganisms that live on or in us and plays a crucial role in the health and development. Commensal species that reside in the intestine ...particularly influence host physiology at local and systemic levels. Multiple sclerosis (MS) is a debilitating autoimmune disorder of the central nervous system for which there is currently no cure. While the cause of MS is unknown, there is a growing body of evidence suggesting that the microbiota can play both pathogenic and protective roles in disease progression. In this review, we provide a brief overview, based on both animal and clinical studies, of the current understanding by which the microbiota may influence MS and discuss opportunities for therapeutic intervention that may alleviate the symptoms associated with this debilitating neuroimmunological disease.
Maintenance of CD4 T cells during chronic infections is vital for limiting pathogen burden and disease recrudescence. Although inhibitory receptor expression by CD4 T cells is commonly associated ...with immune suppression and exhaustion, such cell-intrinsic mechanisms that control activation are also associated with cell survival. Using a mouse model of visceral leishmaniasis (VL), we discovered a subset of lymphocyte activation gene 3 (LAG-3)-expressing CD4 T cells that co-express CXCR5. Although LAG3+CXCR5+ CD4 T cells are present in naive mice, they expand during VL. These cells express gene signatures associated with self-renewal capacity, suggesting progenitor-like properties. When transferred into Rag1−/− mice, these LAG3+CXCR5+ CD4 T cells differentiated into multiple effector types upon Leishmania donovani infection. The transcriptional repressor B cell lymphoma-6 was partially required for their maintenance. Altogether, we propose that the LAG3+CXCR5+ CD4 T cell subset could play a role in maintaining CD4 T cell responses during persistent infections.
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•LAG3+CXCR5+PD-1lo/int CD4 T cells expand during chronic visceral leishmaniasis•These cells express genes associated with self-renewal•LAG3+CXCR5+PD-1lo/int CD4 T cells give rise to multiple CD4 T cell subsets•BCL-6 is partially required for their maintenance
Swaminathan et al. identify a CD4 T cell subset that expresses LAG3+CXCR5+PD-1lo/int and expands during chronic visceral leishmaniasis. These cells display progenitor-like capacity, express genes associated with self-renewal, and differentiate into effector as well as regulatory CD4 T cell subsets, conferring protection upon adoptive transfer.
A number of food allergies (eg, fish, shellfish, and nuts) are lifelong, without any disease-transforming therapies, and unclear in their underlying immunology. Clinical manifestations of food ...allergy are largely mediated by IgE. Although persistent IgE titers have been attributed conventionally to long-lived IgE
plasma cells (PCs), this has not been directly and comprehensively tested.
We sought to evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.
We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments, and in vitro assays to identify mechanisms underlying persistent IgE humoral immunity over almost the entire lifespan of the mouse (18-20 months).
Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titers are not sustained by long-lived IgE
PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE
PC compartment. B-cell reactivation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific germinal centers (23.3 days), IgE
and IgG
PCs (60 and 234.4 days, respectively), and clinically relevant cell-bound IgE (67.3 days).
These findings can explain lifelong food allergies observed in human subjects as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.
The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid ...organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4(+) T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4-producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5(-) PD-1(-) IL-4/GFP(+) CD4(+) T cells after their transfer into naive mice and antigen challenge in vivo.
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