Liver damage and immune responses.

Chronic liver disease (CLD) has massive systemic repercussions including major impacts on the body's immune system. Abnormalities in phenotype, function and numbers of various immune cell subsets have been established by a large number of clinical and pre-clinical studies. The loss of essential immune functions renders CLD-patients exceptionally susceptible to bacterial and viral infections and also impairs the efficacy of vaccination.

Precursors of exhausted T cells are preemptively formed in acute infection.

T cell exhaustion limits effector T cell function in chronic infection and tumors. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found similar T cell populations in the early phase of acute infections.

Obesity differs from diabetes mellitus in antibody and T-cell responses post-COVID-19 recovery.

Objective: Obesity and type 2 diabetes (DM) are risk factors for severe coronavirus disease 2019 (COVID-19) outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with overweight/obesity (Ov/Ob, BMI ≥ 23 kg/m2) and DM in Bangladesh.

Methods: In this cross-sectional study, SARS-CoV-2-specific antibody and T-cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020.

Conditional NKT Cell Depletion in Mice Reveals a Negative Feedback Loop That Regulates CTL Cross-Priming.

NKT cells are unconventional T cells whose biological role is incompletely understood. Similar to TH cells, activated NKT cells can cause dendritic cell (DC) maturation, which is required for effective CTL responses. However, it is unclear whether and how NKT cells affect CTLs downstream of the DC maturation phase.

Cellular immunity to SARS-CoV-2 following intrafamilial exposure in seronegative family members.

Introduction: Family studies of antiviral immunity provide an opportunity to assess virus-specific immunity in infected and highly exposed individuals, as well as to examine the dynamics of viral infection within families. Transmission of SARS-CoV-2 between family members represented a major route for viral spread during the early stages of the pandemic, due to the nature of SARS-CoV-2 transmission through close contacts.

Methods: Here, humoral and cellular immunity is explored in 264 SARS-CoV-2 infected, exposed or unexposed individuals from 81 families in the United Kingdom sampled in the winter of 2020 before widespread vaccination and infection.

MAITs and their mates: "Innate-like" behaviors in conventional and unconventional T cells.

Most CD4 and CD8 T cells are restricted by conventional major histocompatibility complex (MHC) molecules and mount TCR-dependent adaptive immune responses. In contrast, MAIT, iNKT, and certain γδ TCR bearing cells are characterized by their abilities to recognize antigens presented by unconventional antigen-presenting molecules and to mount cytokine-mediated TCR-independent responses in an "innate-like" manner. In addition, several more diverse T-cell subsets have been described that in a similar manner are restricted by unconventional antigen-presenting molecules but mainly depend on their TCRs for activation.

Interferon-induced IL-10 drives systemic T-cell dysfunction during chronic liver injury.

Background & Aims: Patients with chronic liver disease (CLD), including cirrhosis, are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Hallmarks of CLD and cirrhosis include microbial translocation and elevated levels of type I interferon (IFN-I). We aimed to investigate the relevance of microbiota-induced IFN-I in the impaired adaptive immune responses observed in CLD.

Prostaglandins differentially modulate mucosal-associated invariant T-cell activation and function according to stimulus.

Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell type conserved in many mammals and especially abundant in humans. Their semi-invariant T-cell receptor (TCR) recognizes the major histocompatibility complex-like molecule MR1 presenting riboflavin intermediates associated with microbial metabolism. Full MAIT cell triggering requires costimulation via cytokines, and the cells can also be effectively triggered in a TCR-independent manner by cytokines [e.

A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice.

Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells.

Emerging features of MAIT cells and other unconventional T cell populations in human viral disease and vaccination.

MAIT cells are one representative of a group of related unconventional or pre-set T cells, and are particularly abundant in humans. While these unconventional T cell types, which also include populations of Vδ2 cells and iNKT cells, recognise quite distinct ligands, they share functional features including the ability to sense "danger" by integration of cytokine signals. Since such signals are common to many human pathologies, activation of MAIT cells in particular has been widely observed.

Booster Vaccination Against SARS-CoV-2 Induces Potent Immune Responses in People With Human Immunodeficiency Virus.

Background: People with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) with good CD4 T-cell counts make effective immune responses following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are few data on longer term responses and the impact of a booster dose.

Methods: Adults with HIV were enrolled into a single arm open label study.

Human MAIT cells respond to and suppress HIV-1.

Human MAIT cells sit at the interface between innate and adaptive immunity, are polyfunctional and are capable of killing pathogen infected cells via recognition of the Class IB molecule MR1. MAIT cells have recently been shown to possess an antiviral protective role in vivo and we therefore sought to explore this in relation to HIV-1 infection. There was marked activation of MAIT cells in vivo in HIV-1-infected individuals, which decreased following ART.

T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers.

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus.

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report.

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement.

Human MAIT Cell Activation In Vitro.

Mucosal-associated invariant T (MAIT) cells are an abundant innate-like T cell subset in humans, enriched in mucosal tissues and the liver. MAIT cells express a semi-invariant T cell receptor (TCR) and recognize microbial-derived riboflavin metabolites presented on the MHC Class I-like molecule MR1. In addition to activation via the TCR, MAIT cells can also be activated in response to cytokines such as IL-12 and IL-18, in contrast to conventional T cells.

TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions.

MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8 MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A.

Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice.

Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes (Idd) loci and candidate genes, one of them being Cd101.

Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis.

Objective: Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.

Methods: Experimental liver fibrosis in mice induced by bile duct ligation or CCl application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.

Results: In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver.