ORCID Profile
0000-0002-7217-5729
Current Organisation
Benaroya Research Institute
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Publisher: Elsevier BV
Date: 2020
Publisher: Cold Spring Harbor Laboratory
Date: 10-06-2020
DOI: 10.1101/2020.06.05.20114876
Abstract: Clostridioides difficile is a leading cause of infectious diarrhea and an urgent antimicrobial resistant threat. Symptoms are caused by its toxins, TcdA and TcdB, with many patients developing recurrent C. difficile infection (CDI), requiring fecal microbiota transplant (FMT). Antibody levels have not been useful in predicting patient outcomes, which is an unmet need. We aimed to characterize T cell-mediated immunity to C. difficile toxins and assess how these responses were affected by FMT. We obtained blood s les from patients with newly acquired CDI, recurrent CDI (with a subset receiving FMT), inflammatory bowel disease with no history of CDI, and healthy in iduals (controls). Toxin-specific CD4 + T cell responses were analysed using a whole blood flow cytometry antigen-induced marker assay. Serum antibodies were measured by ELISA. Tetramer guided mapping was used to identify HLA-II-restricted TcdB epitopes and DNA was extracted from TcdB-specific CD4 + T cells for TCR repertoire analysis by Sanger sequencing. CD4 + T cell responses to C. difficile toxins were functionally erse. Compared to controls, in iduals with CDI, or inflammatory bowel disease had significantly higher frequencies of TcdB-specific CD4 + T cells. Subjects with recurrent CDI had reduced proportions of TcdB-specific CD4 + Th17 cells, FMT reversed this deficit and increased toxin-specific antibody production. These data suggest that effective T cell immunity to C. difficile requires the development of Th17 cells. In addition, they show that an unknown aspect of the therapeutic effect of FMT may be enhanced T and B cell-mediated immunity to TcdB.
Publisher: Cold Spring Harbor Laboratory
Date: 13-04-2021
DOI: 10.1101/2021.04.07.21255038
Abstract: Antibody production following vaccination can provide protective immunity to subsequent infection from pathogens such as influenza. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at risk groups. Here, by studying the breadth of anti-hemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper cells (cTfh) cells are the best predictor of high titre antibody responses. Using MHC class II tetramers we demonstrate that HA-specific cTfh cells can derived from pre-existing memory CD4 + T cells and have a erse TCR repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together this suggests that strategies that temporarily d en inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people. Antibody production upon vaccination requires antigen-specific cTfh cells whose formation is suppressed by pro-inflammatory cytokine signalling.
Publisher: Springer Science and Business Media LLC
Date: 06-05-2019
No related grants have been discovered for Eddie James.