Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells.

MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I-related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.

Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses.

Mucosal-associated invariant T (MAIT) cells use canonical semi-invariant T cell receptors (TCR) to recognize microbial riboflavin precursors displayed by the antigen-presenting molecule MR1. The extent of MAIT TCR crossreactivity toward physiological, microbially unrelated antigens remains underexplored. We describe MAIT TCRs endowed with MR1-dependent reactivity to tumor and healthy cells in the absence of microbial metabolites. MAIT cells bearing TCRs crossreactive toward self are rare but commonly found within healthy donors and display T-helper-like functions in vitro. Experiments with MR1-tetramers loaded with distinct ligands revealed significant crossreactivity among MAIT TCRs both ex vivo and upon in vitro expansion. A canonical MAIT TCR was selected on the basis of extremely promiscuous MR1 recognition. Structural and molecular dynamic analyses associated promiscuity to unique TCRß-chain features that were enriched within self-reactive MAIT cells of healthy individuals. Thus, self-reactive recognition of MR1 represents a functionally relevant indication of MAIT TCR crossreactivity, suggesting a potentially broader role of MAIT cells in immune homeostasis and diseases, beyond microbial immunosurveillance.

mHealth intervention to improve quality of life in patients with chronic diseases during the COVID-19 crisis in Paraguay: A study protocol for a randomized controlled trial.

BACKGROUND: Patients with chronic disease represent an at-risk group in the face of the COVID-19 crisis as they need to regularly monitor their lifestyle and emotional management. Coping with the illness becomes a challenge due to supply problems and lack of access to health care facilities. It is expected these limitations, along with lockdown and social distancing measures, have affected the routine disease management of these patients, being more pronounced in low- and middle-income countries with a flawed health care system. OBJECTIVES: The purpose of this study is to describe a protocol for a randomized controlled trial to test the efficacy of the Adhera® MejoraCare Digital Program, an mHealth intervention aimed at improving the quality of life of patients with chronic diseases during the COVID-19 outbreak in Paraguay. METHOD: A two-arm randomized controlled trial will be carried out, with repeated measures (baseline, 1-month, 3-month, 6-month, and 12-month) under two conditions: Adhera® MejoraCare Digital Program or waiting list. The primary outcome is a change in the quality of life on the EuroQol 5-Dimensions 3-Levels Questionnaire (EQ-5D-3L). Other secondary outcomes, as the effect on anxiety and health empowerment, will be considered. All participants must be 18 years of age or older and meet the criteria for chronic disease. A total of 96 participants will be recruited (48 per arm). CONCLUSIONS: It is expected that the Adhera® MejoraCare Digital Program will show significant improvements in quality of life and emotional distress compared to the waiting list condition. Additionally, it is hypothesized that this intervention will be positively evaluated by the participants in terms of usability and satisfaction. The findings will provide new insights into the viability and efficacy of mHealth solutions for chronic disease management in developing countries and in times of pandemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT04659746.

Retrocyte Display® technology: generation and screening of a high diversity cellular antibody library.

Over the last nearly three decades in vitro display technologies have played an important role in the discovery and optimization of antibodies and other proteins for therapeutic applications. Here we describe the use of retroviral expression technology for the display of full-length IgG on B lineage cells in vitro with a hallmark of a tight and stable genotype to phenotype coupling. We describe the creation of a high-diversity (>1.0E09 different heavy- and light-chain combinations) cell displayed fully human antibody library from healthy donor-derived heavy- and light-chain gene libraries, and demonstrate the recovery of high affinity target-specific antibodies from this library by staining of cells with a labeled target antigen and their magnetic- and flow cytometry-based cell sorting. The present technology represents a further evolution in the discovery of full-length, fully human antibodies using mammalian display, and is termed Retrocyte Display® (Retroviral B lymphocyte Display).

Primary human keratinocytes efficiently induce IL-1-dependent IL-17 in CCR6+ T cells.

Keratinocytes and activated T cells interact in skin inflammation by virtue of chemokines and cytokines. T cell-derived IL-17 has been described to play an important role in the course of psoriatic inflammation. In this study, we addressed how keratinocytes influence the secretion of IL-17 in autologous T cell subsets. We found that a co-culture of autologous keratinocytes and T cell-receptor-stimulated T cells markedly enhanced the production of IL-17. Besides the importance of direct cell contact, this effect was mainly mediated by IL-1 and could be blocked by the IL-1 antagonist anakinra. An additional increase in IL-17 production by IL-23 was only seen in the presence of IL-1, which thus plays a permissive role for the action of IL-23. Importantly, co-culture of keratinocytes with CCR6+ CD4+ T cells that are enriched for Th17 cells resulted in significantly higher IL-17 production compared to co-culture with CD4+ T cells.