Invariant natural killer T cells in autoimmune cholangiopathies: Mechanistic insights and therapeutic implications.

Invariant natural killer T cells (iNKT cells) constitute a specialized subset of lymphocytes that bridges innate and adaptive immunity through a combination of traits characteristic of both conventional T cells and innate immune cells. iNKT cells are characterized by their invariant T cell receptors and discerning recognition of lipid antigens, which are presented by the non-classical MHC molecule, CD1d. Within the hepatic milieu, iNKT cells hold heightened prominence, contributing significantly to the orchestration of organ homeostasis.

Biological interactions of polystyrene nanoplastics: Their cytotoxic and immunotoxic effects on the hepatic and enteric systems.

As emerging pollutants in the environment, nanoplastics (NPs) can cross biological barriers and be enriched in organisms, posing a greatest threat to the health of livestock and humans. However, the size-dependent toxic effects of NPs in higher mammals remain largely unknown. To determine the size-dependent potential toxicities of NPs, we exposed mouse (AML-12) and human (L02) liver cell lines in vitro, and 6-week-old C57BL/6 mice (well-known preclinical model) in vivo to five different sizes of polystyrene NPs (PS-NPs) (20, 50, 100, 200 and 500 nm).

Intestinal colonization regulates systemic anti-commensal immune sensitivity and hyperreactivity.

Healthy host-microbial mutualism with our intestinal microbiota relies to a large degree on compartmentalization and careful regulation of adaptive mucosal and systemic anti-microbial immune responses. However, commensal intestinal bacteria are never exclusively or permanently restricted to the intestinal lumen and regularly reach the systemic circulation. This results in various degrees of commensal bacteremia that needs to be appropriately dealt with by the systemic immune system.

The impact of the gut microbiota on T cell ontogeny in the thymus.

The intestinal microbiota is critical for the development of gut-associated lymphoid tissues, including Peyer's patches and mesenteric lymph nodes, and is instrumental in educating the local as well as systemic immune system. In addition, it also impacts the development and function of peripheral organs, such as liver, lung, and the brain, in health and disease. However, whether and how the intestinal microbiota has an impact on T cell ontogeny in the hymus remains largely unclear.

Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity.

Peptide MHC class II-based (pMHCII-based) nanomedicines trigger the formation of multicellular regulatory networks by reprogramming autoantigen-experienced CD4+ T cells into autoimmune disease-suppressing T regulatory type 1 (TR1) cells. We have shown that pMHCII-based nanomedicines displaying liver autoimmune disease-relevant yet ubiquitously expressed antigens can blunt various liver autoimmune disorders in a non-disease-specific manner without suppressing local or systemic immunity against infectious agents or cancer. Here, we show that such ubiquitous autoantigen-specific T cells are also awakened by extrahepatic tissue damage and that the corresponding TR1 progeny can suppress experimental autoimmune encephalomyelitis (EAE) and pancreatic β cell autoreactivity.

Suppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines.

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells.

A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress Colitis.

The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut.

Peptide-MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices.

We have shown that nanoparticles (NPs) can be used as ligand-multimerization platforms to activate specific cellular receptors in vivo. Nanoparticles coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHC) blunted autoimmune responses by triggering the differentiation and expansion of antigen-specific regulatory T cells in vivo. Here, we define the engineering principles impacting biological activity, detail a synthesis process yielding safe and stable compounds, and visualize how these nanomedicines interact with cognate T cells.

The cross-priming capacity and direct presentation potential of an autoantigen are separable and inversely related properties.

We investigated whether a prevalent epitope of the β-cell-specific autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP206-214) reaches regional Ag-presentation pathways via unprocessed polypeptide chains, as free IGRP206-214 peptide or via preformed IGRP206-214/K(d) complexes. This was accomplished by expressing bacterial artificial chromosome transgenes encoding wild-type (stable) or ubiquitinated (unstable) forms of IGRP in IGRP-deficient NOD mice carrying MHC class I-deficient β-cells, dendritic cells, or B cells. We investigated the ability of the pancreatic lymph nodes of these mice to prime naive IGRP206-214-reactive CD8(+) T cells in vivo, either in response to spontaneous Ag shedding, or to synchronized forms of β-cell necrosis or apoptosis.

CD154 and IL-2 signaling of CD4+ T cells play a critical role in multiple phases of CD8+ CTL responses following adenovirus vaccination.

Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8(+) cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4(+) T cell-provided signals in the development of functional CD8(+) CTL responses remain unclear. To explore CD4(+) T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4(+) T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector.

Bluetongue virus - 23 stimulates inducible nitric oxide synthase expression and nitric oxide production in mononuclear cells of blood and/or regional lymphoid organs.

Mononuclear leukocytes of peripheral blood mononuclear cells (PBMCs) and regional lymphoid organs (RLOs) play a critical role in primary BTV replication and subsequent viral dissemination to distant systemic organs. The lesions in animals develop primarily as a result of vascular insult, presumably induced by the activity of viral and/or proinflammatory vasoactive mediators. Hence, the current study was designed in sheep to investigate the responses of potent vasoactivators, inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) in mononuclear leukocytes of PBMCs and RLOs.

Novel CD8+ T cell-based vaccine stimulates Gp120-specific CTL responses leading to therapeutic and long-term immunity in transgenic HLA-A2 mice.

The limitations of highly active anti-retroviral therapy have necessitated the development of alternative therapeutics for human immunodeficiency virus type-1 (HIV-1)-infected patients with dysfunctional dendritic cells (DCs) and CD4(+) T cell deficiency. We previously demonstrated that HIV-1 Gp120-specific T cell-based Gp120-Texo vaccine by using ConA-stimulated C57BL/6 (B6) mouse CD8(+) T (ConA-T) cells with uptake of pcDNA(Gp120)-transfected B6 mouse DC line DC2.4 (DC2.

A comparison of intradermal and intravenous inoculation of bluetongue virus serotype 23 in sheep for clinico-pathology, and viral and immune responses.

The pathogenesis of bluetongue (BT) could vary with route of inoculation. Using laboratory-passaged moderately virulent bluetongue virus serotype 23 (BTV-23), one of the most prevalent Indian serotype, we investigated the pathogenesis of BT in intradermally (ID) and intravenously (IV) inoculated native sheep. The ID inoculation resulted in relatively increased clinical signs and lesions in many organs as compared to IV inoculation.

GP120-specific exosome-targeted T cell-based vaccine capable of stimulating DC- and CD4(+) T-independent CTL responses.

The limitations of highly active anti-retroviral therapy (HAART) have necessitated the development of alternative therapeutics. In this study, we generated ovalbumin (OVA)-pulsed and pcDNAgp120-transfected dendritic cell (DC)-released exosomes (EXOova and EXOgp120) and ConA-stimulated C57BL/6 CD8(+) T cells. OVA- and Gp120-Texo vaccines were generated from CD8(+) T cells with uptake of EXOova and EXOgp120, respectively.

The measurement of three cytokine transcripts in naïve and sensitized ovine peripheral blood mononuclear cells following in vitro stimulation with bluetongue virus serotype-23.

Bluetongue (BT), a serious disease of sheep and some wild ruminants, is caused by bluetongue virus (BTV), a member of the family, Reoviridae. The current research thrust for controlling BT is on development of efficient vaccines, necessitating clear understanding of ovine immunology. At present, comparative studies on cytokine gene expression profiles of naïve and BTV-sensitized peripheral blood mononuclear cells (PBMC) in sheep have not been clearly understood.

Apoptosis and immuno-suppression in sheep infected with bluetongue virus serotype-23.

The role of apoptosis in pathogenesis of bluetongue (BT) has been suggested from various in vitro studies. However, to date, no clear data are available regarding BTV-induced apoptosis and its consequences in natural host, sheep. In the present study, bluetongue virus (BTV)-induced apoptosis was studied in sheep blood and splenic mononuclear cells by analyzing annexin(+)-propidium iodide(-) early apoptotic cells, DNA ladder pattern, and caspase-3 gene expression.

Cell-mediated immune response and cross-protective efficacy of binary ethylenimine-inactivated bluetongue virus serotype-1 vaccine in sheep.

Bluetongue is a serious hemorrhagic disease of sheep, cattle and other ruminants causing economic losses worldwide. Recent invasion of multiple bluetongue virus serotypes (BTV) in various countries warrants immediate development of efficacious vaccine that targets more than one serotype. In the present study, the cross-protective efficacy of binary ethylenimine (BEI)-inactivated BTV-1 vaccine was evaluated in Indian native sheep against virulent heterologous BTV-23 serotype challenge.