Biallelic mutations in IRF8 impair human NK cell maturation and function.

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease.

Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation.

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome.

IL-10-induced gp130 expression in mouse mast cells permits IL-6 trans-signaling.

It is reported that human and mouse mast cells express the IL-27R, which consists of WSX-1 (the IL-27Rα subunit) and the signal-transducing subunit gp130. Although it has been proposed that IL-27 may negatively regulate mast cell-dependent, immediate hypersensitivity responses directly, this has yet to be examined specifically. We found that mouse BMMC and primary peritoneal mast cells are unresponsive to IL-27.

Leucine-rich repeat (in Flightless I) interacting protein-1 regulates a rapid type I interferon response.

The cell autonomous response to viral infection is carefully regulated to induce type I interferons (IFNs), which in turn induce the establishment of an antiviral state. Leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) and LRRFIP2 are 2 related proteins that have been identified as interacting with MyD88 and Flightless I homolog, a leucine-rich repeat protein. LRRFIP2 positively regulates NFκB and macrophage cytokine production after lipopolysaccharide, but less is known about LRRFIP1.

Cooperation of adapter molecules in proximal signaling cascades during allergic inflammation.

Activation of mast cells through their high-affinity immunoglobulin E receptor (FcepsilonRI) plays an important role in allergic disorders. Other mast cell-activating stimuli, such as Toll-like receptor (TLR) ligands, synergize with FcepsilonRI to enhance allergic inflammation. Thus, there is much interest in understanding how signaling occurs downstream of these receptors.

MyD88 plays a critical T cell-intrinsic role in supporting CD8 T cell expansion during acute lymphocytic choriomeningitis virus infection.

During acute lymphocytic choriomeningitis virus (LCMV) infection, CD8 T cells rapidly expand and differentiate into effectors that are required for viral clearance. The accumulation of activated T cells is greatly reduced in mice lacking the adaptor molecule MyD88. Although MyD88 has generally been considered to indirectly regulate adaptive immune responses by controlling inflammatory cytokine production and Ag presentation in innate immune cells, in this study, we identify an unappreciated cell-intrinsic role for MyD88 in LCMV-specific CD8 T cells.

Granulomatous-lymphocytic interstitial lung disease associated with common variable immunodeficiency: CT findings.

Purpose: To evaluate computed tomography (CT) scans of individuals with granulomatous-lymphocytic interstitial lung disease and common variable immunodeficiency (CVID) to determine if there are imaging features that distinguish this manifestation of CVID from the more usual imaging findings.

Materials And Methods: A review of the CVID population at our institution identified a series of 5 patients with CVID who had documented granulomatous disease on biopsy specimens. The initial and follow-up CT examinations were reviewed by 2 radiologists, and imaging findings in the chest and abdomen were tabulated by consensus.

Mechanisms underlying blockade of allograft acceptance by TLR ligands.

Immune activation via TLRs is known to prevent transplantation tolerance in multiple animal models. To investigate the mechanisms underlying this barrier to tolerance induction, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4(+)Foxp3(+) T regulatory cells (Tregs), and that the TLR9 ligand CpG prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo.

T cell expression of MyD88 is required for resistance to Toxoplasma gondii.

Resistance to Toxoplasma gondii depends on dendritic cells to recognize this pathogen and secrete IL-12, in turn promoting IFN-gamma production from responding T cells. The adaptor protein, myeloid differentiation primary-response gene 88 (MyD88), is important for most Toll-like receptor (TLR) signaling, as well as IL-1R/IL-18R signals. There is considerable evidence that MyD88 is required for the innate sensing of T.

Atopic characteristics of adult patients with eosinophilic esophagitis.

Background & Aims: The association of sensitization to food allergens, atopic disorders, and eosinophilic esophagitis (EE) is well known in children, but not in adults. Our purpose was to identify the spectrum of specific allergic sensitivities to environmental and food allergens within a series of adult patients with EE.

Methods: The case series consisted of 23 adult patients with biopsy-proven EE referred for allergy evaluation at an academic clinic.

1. Lymphocytes.

Lymphocytes are white blood cells uniform in appearance but varied in function and include T, B, and natural killer cells. These cells are responsible for antibody production, direct cell-mediated killing of virus-infected and tumor cells, and regulation of the immune response. Advances in immunology have led to the characterization of newly appreciated effector populations such as IL-17-producing T cells, T cells with regulatory function, and natural killer T cells, thus revising established paradigms.

Presentation of Toxoplasma gondii antigens via the endogenous major histocompatibility complex class I pathway in nonprofessional and professional antigen-presenting cells.

Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T.

The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes.

5,6-Di-methylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity. Although classified as a "vascular disrupting agent," we have recently conducted studies showing that DMXAA has remarkable efficacy in a range of tumors, working primarily as an immune modulator that activates tumor-associated macrophages and induces a subsequent CD8(+) T-cell-mediated response. To more completely analyze the effect of DMXAA on CD8(+) T-cell generation, we treated mice bearing tumors derived from EG7 thymoma cells that express the well-characterized chicken ovalbumin neotumor antigen.

The innate immune system in allograft rejection and tolerance.

As T cells alone are both necessary and sufficient for the rejection of virtually all allogeneic tissues, much of transplantation immunology has focused on cells of the adaptive immune system. During the past decade, advances in our understanding of innate responses to pathogen-associated molecules have spurred a "rediscovery" of innate immunity. Fueled by this, an increasing body of literature has emerged in which the role of the innate immune system in allograft rejection and tolerance has been examined more closely.

Progressive multifocal leukoencephalopathy in a patient with common variable immunodeficiency and abnormal CD8+ T-cell subset distribution.

Background: Patients with primary hypogammaglobulinemia have been reported to have encephalopathy, but progressive multifocal leukoencephalopathy (PML) due to JC virus reactivation is a rare cause.

Objective: To provide the clinical details and case discussion of a patient diagnosed as having common variable immunodeficiency (CVID) who has progressive neurodegenerative symptoms and was found to have PML and an abnormal CD8+ T-cell subset distribution.

Methods: A detailed case report providing the patient's immunodeficiency history, diagnostic evaluation, and medical management and a review of related literature.

CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells.

Toll-like receptor (TLR) ligands are notable for their ability to induce APC maturation, which in turn facilitates optimal T cell mediated immune responses. Toll-like receptor ligands, such as CpG DNA, can also modulate immune responses by blocking the suppressive effects of CD4+CD25+ regulatory T cells (Tregs). Recently, we have demonstrated that CpG DNA, in addition to its actions on APCs and Tregs, can provide direct costimulatory signals to CD4+CD25- T cells.

The adaptor molecule MyD88 activates PI-3 kinase signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-mediated costimulation.

While T cells respond directly to toll-like receptor (TLR) agonists, TLR-signaling pathways in T cells are poorly characterized. Here we demonstrate in CD4(+) T cells that CpG DNA directly enhances proliferation, prevents anergy, and augments humoral responses to a T cell-dependent antigen by a Myeloid differentiation primary-response protein 88 (MyD88) and Phosphatidylinositol 3-kinase (PI-3 kinase)-dependent pathway. PI-3 kinase activation required a putative Src-homology domain (SH2) binding motif in the MyD88 Toll-Like or IL-1 Receptor (TIR) domain.

Constitutive activation of STAT5 supersedes the requirement for cytokine and TCR engagement of CD4+ T cells in steady-state homeostasis.

The transcription factor STAT5 is one of several signaling mediators activated via common gamma-chain cytokine receptors. As such, it plays an important role in lymphocyte survival and proliferation during normal homeostasis as well as under lymphopenic conditions. Transgenic mice expressing a constitutively activated form of STAT5b have been shown previously to contain increased numbers of peripheral CD4+CD25- T cells.