Gamma interferon-inducible lysosomal thioreductase (GILT) ablation renders mouse fibroblasts sensitive to dengue virus replication.

Dengue viruses (DENV), members of mosquito-borne Flaviviruses, are human pathogens of global significance. The virus enters the host cell through endocytosis and uncoating subsequent to a low pH-triggered conformational change of E protein in endosomes. The endosomes are active in antigen processing and the key enzyme involved is the gamma interferon-inducible lysosomal thiol reductase (GILT).

A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-γ-inducible lysosomal thiol reductase-free mice.

IFN-γ-inducible lysosomal thiol reductase (GILT) is an enzyme located in the Lamp-2-positive compartments of APC. GILT(-/-) mice are phenotypically normal, but their T cells exhibit reduced proliferation to several exogenously administered Ags that include cysteine residues and disulfide bonds. We undertook the present studies to determine if GILT(-/-) mice would process exogenously administered myelin oligodendrocyte glycoprotein (MOG), which contains disulfide bonds, to generate experimental autoimmune encephalomyelitis (EAE) to the endogenous protein.

Lysosomal thiol reductase negatively regulates autophagy by altering glutathione synthesis and oxidation.

Redox regulation is critical for a number of cellular functions and has been implicated in the etiology and progression of several diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer. It has been shown that, in the absence of gamma-interferon inducible lysosomal thiol reductase (GILT), cells are under increased oxidative stress with higher superoxide levels and decreased stability, expression, and function of mitochondrial manganese superoxide dismutase (SOD2). Here, we further elucidate the role of GILT in the homeostatic regulation of oxidative stress.

Signal transducer and activator of transcription 1 negatively regulates constitutive gamma interferon-inducible lysosomal thiol reductase expression.

Gamma interferon-inducible lysosomal thiol reductase (GILT) is an enzyme that catalyzes thiol bond reduction and plays an important role in the early steps of antigen processing. The key factor involved in the regulation of GILT expression upon cell stimulation with interferon-γ (IFN-γ) is signal transducer and activator of transcription 1 (STAT1). In this study, we examined the role of STAT1 in regulating the constitutive expression of GILT.

Comparative quantitative mass spectrometry analysis of MHC class II-associated peptides reveals a role of GILT in formation of self-peptide repertoire.

Gamma interferon Inducible Lysosomal Thiol reductase (GILT) is a unique lysosomal reductase that reduces disulfide bonds of endocytosed proteins. Lack of GILT clearly decreases CD4 T cell-antigen specific responses against some epitopes of antigens containing disulfide bonds, but not to proteins with few or no disulfide bridges. Hence, global impact of GILT on antigen presentation is currently not well understood.

Cutting edge: developmental up-regulation of IFN-gamma-inducible lysosomal thiol reductase expression leads to reduced T cell sensitivity and less severe autoimmunity.

Reactivity to self-peptide/MHC complexes is required for selection of the TCR repertoire in the thymus but can also promote autoimmunity. Reduced TCR sensitivity of mature T cells is thought to help control the autoreactivity in peripheral T cells. The molecular basis for reduced sensitivity of peripheral T cells is not known.

B cells induce tolerance by presenting endogenous peptide-IgG on MHC class II molecules via an IFN-gamma-inducible lysosomal thiol reductase-dependent pathway.

We have previously demonstrated that splenic B cells, transduced with peptide-IgG fusion proteins, are efficient tolerogenic APCs in vivo. Specific hyporesponsiveness to epitopes encoded in the peptide-IgG fusion protein has been achieved to over one dozen Ags, and clinical efficacy has been established in animal models for several autoimmune diseases and hemophilia. Previous studies also demonstrated that tolerance in this system requires MHC class II expression by the transduced B cells.

An unexpected functional link between lysosomal thiol reductase and mitochondrial manganese superoxide dismutase.

Gamma interferon-inducible thiol reductase (GILT) is an enzyme involved in the initial steps of antigen processing and presentation. Recently we have shown that GILT is also expressed in mouse T cells, where it exerts an inhibitory role on T cell activation. In this study, we identified mitochondrial manganese superoxide dismutase (SOD2) as one of the key intermediaries affected by GILT expression in fibroblasts.

Inhibitory role of IFN-gamma-inducible lysosomal thiol reductase in T cell activation.

IFN-gamma-inducible lysosomal thiol reductase (GILT) is a unique thiol reductase with optimal enzymatic activity at low pH. GILT plays a crucial role in unfolding the antigenic proteins in preparation for their proteolytic cleavage and presentation of resulting peptides by MHC class II. In this study, we demonstrate that GILT is expressed in T lymphocytes and that it has an APC-nonrelated role in the regulation of T cell activation.

Differential requirements for endosomal reduction in the presentation of two H2-E(d)-restricted epitopes from influenza hemagglutinin.

We examined the role of reduction in the presentation of two H2-E(d)-restricted epitopes (site 1 epitope (S1) and site 3 epitope (S3)) occupying distinct domains of the influenza hemagglutinin major subunit that contains four intrachain disulfide bonds and is connected to the virion by one interchain bond. S3 is situated within the stalk region that unfolds in response to mild acidification, and loads onto recycling H2-E(d) in the early endosome, while S1, located in the structurally constrained globular domain, loads onto nascent H2-E(d) in the late endosome. Predicting dependence upon reduction for either epitope seemed plausible but the results from several approaches were clear: presentation of S1 but not S3 is reduction dependent.

Absence of gamma-interferon-inducible lysosomal thiol reductase in melanomas disrupts T cell recognition of select immunodominant epitopes.

Long-lasting tumor immunity requires functional mobilization of CD8+ and CD4+ T lymphocytes. CD4+ T cell activation is enhanced by presentation of shed tumor antigens by professional antigen-presenting cells (APCs), coupled with display of similar antigenic epitopes by major histocompatibility complex class II on malignant cells. APCs readily processed and presented several self-antigens, yet T cell responses to these proteins were absent or reduced in the context of class II+ melanomas.

Factors influencing the patterns of T lymphocyte allorecognition.

Background: Strong alloreactive T cell responses are a menace in transplantation surgery and their menagement requires understanding the basis of alloreactivity. Alloantigen recognition can be peptide independent, peptide specific, or peptide dependent. The mechanisms influencing each recognition pattern are largely unknown.

Disulfide reduction in major histocompatibility complex class II-restricted antigen processing by interferon-gamma-inducible lysosomal thiol reductase.

Constitutively expressed in antigen-presenting cells (APCs), interferon-gamma-inducible lysosomal thiol reductase (GILT) catalyzes disulfide bond reduction under acidic conditions. GILT contains a CXXC motif similar to the WCGH/PCK motif of proteins in the thioredoxin family. This class of enzymes catalyzes, at a neutral pH, dithiol oxidation, disulfide bond reduction, and disulfide bond isomerization.