Cellular fibronectin, which contains an alternatively spliced exon encoding type III repeat extra domain A (EDA), is produced in response to tissue injury. Fragments of fibronectin have been implicated in physiological and pathological processes, especially tissue remodeling associated with inflammation. Because EDAcontaining fibronectin fragments produce cellular responses similar to those provoked by bacterial lipopolysaccharide (LPS), we examined the ability of recombinant EDA to activate Toll-like receptor 4 (TLR4), the signaling receptor stimulated by LPS. We found that recombinant EDA, but not other recombinant fibronectin domains, activates human TLR4 expressed in a cell type (HEK 293 cells) that normally lacks this Toll-like receptor. EDA stimulation of TLR4 was dependent upon co-expression of MD-2, a TLR4 accessory protein. Unlike LPS, the activity of EDA was heat-sensitive and persisted in the presence of the LPS-binding antibiotic polymyxin B and a potent LPS antagonist, E5564, which completely suppressed LPS activation of TLR4. These observations provided a mechanism by which EDA-containing fibronectin fragments promote expression of genes involved in the inflammatory response.
SummaryCD1d-restricted natural killer T cells (NKT cells) possess a wide range of effector and regulatory activities that are related to their ability to secrete both T helper 1 (Th1) cell- and Th2 cell-type cytokines. We analyzed presentation of NKT cell activating α galactosylceramide (αGalCer) analogs that give predominantly Th2 cell-type cytokine responses to determine how ligand structure controls the outcome of NKT cell activation. Using a monoclonal antibody specific for αGalCer-CD1d complexes to visualize and quantitate glycolipid presentation, we found that Th2 cell-type cytokine-biasing ligands were characterized by rapid and direct loading of cell-surface CD1d proteins. Complexes formed by association of these Th2 cell-type cytokine-biasing αGalCer analogs with CD1d showed a distinctive exclusion from ganglioside-enriched, detergent-resistant plasma membrane microdomains of antigen-presenting cells. These findings help to explain how subtle alterations in glycolipid ligand structure can control the balance of proinflammatory and anti-inflammatory activities of NKT cells.
Activation of CD1d-restricted invariant NKT (iNKT) cells by α-galactosylceramide (αGalCer) significantly suppresses development of diabetes in NOD mice. The mechanisms of this protective effect are complex, involving both Th1 and Th2 cytokines and a network of regulatory cells including tolerogenic dendritic cells. In the current study, we evaluated a newly described synthetic αGalCer analog (C20:2) that elicits a Th2-biased cytokine response for its impact on disease progression and immunopathology in NOD mice. Treatment of NOD mice with αGalCer C20:2 significantly delayed and reduced the incidence of diabetes. This was associated with significant suppression of the late progression of insulitis, reduced infiltration of islets by autoreactive CD8+ T cells, and prevention of progressive disease-related changes in relative proportions of different subsets of dendritic cells in the draining pancreatic lymph nodes. Multiple favorable effects observed with αGalCer C20:2 were significantly more pronounced than those seen in direct comparisons with a closely related analog of αGalCer that stimulated a more mixed pattern of Th1 and Th2 cytokine secretion. Unlike a previously reported Th2-skewing murine iNKT cell agonist, the αGalCer C20:2 analog was strongly stimulatory for human iNKT cells and thus warrants further examination as a potential immunomodulatory agent for human disease.
Natural killer T (NKT) cells are a heterogeneous group of
T cells that share properties characteristic of both T cells
and NK cells and possess a variety of unusual properties
with regard to antigen recognition and function. Many of
these cells recognize the non-polymorphic CD1d molecule,
an antigen-presenting molecule that binds self- and
foreign lipids. The best known subset of CD1d-dependent
NKT cells expresses an invariant T cell receptor a
(TCR-a) chain. These are referred to as type I or invariant
NKT cells (iNKT cells). These cells, which are the main
focus of the current review, are conserved between humans
and mice. Detailed work in mouse models has implicated
iNKT cells in many immunological processes,
and related studies in humans suggest important roles in
health and disease. By virtue of their ability to produce a
variety of immunoregulatory cytokines and to acquire a
broad spectrum of effector activities, iNKT cells may
both induce or suppress immune reactions in healthy
and pathologic settings. We review the role of iNKT cells
in the induction of tolerance to solid organ and hematologic
transplants and malignancies, as well as their importance
in maintaining normal self-tolerance and involvement
in autoimmune diseases.
Human herpesvirus 6 (HHV-6) is a common pathogen among children, classically presenting as fever and rash that resolve without specific therapy (exanthem subitum or roseola infantum). Also identified as a pathogen in hematopoietic cell transplant and solid organ transplant (SOT) recipients, it has been recognized as a cause of limbic encephalitis, characterized by confusion and amnesia, with magnetic resonance imaging findings of T2 hyperintensity of the amygdala and hippocampus. We report a case of limbic encephalitis associated with HHV-6 infection in a liver transplant recipient, and we review previously reported cases of HHV-6 encephalitis in SOT recipients.
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