Barbara Kronsteiner-Dobramysl Poster 2025

Dr Barbara Kronsteiner-Dobramysl

University of Oxford, UK

Features of T-cell dysfunction contributing to disease susceptibility in diabetes mellitus: implications for vaccine design

Poster Abstract

Background: Diabetes mellitus (DM) is a major risk factor for infection with a 12- and 3-fold increased risk of acquiring melioidosis and tuberculosis, respectively. The prevalence of DM is rapidly increasing worldwide with the highest burden seen in low- and middle-income countries, areas of high infectious disease burden. The underlying features of susceptibility to infection in DM are multifaceted including altered metabolism and defects in the myeloid compartment. A better understanding of T-cell responses especially the contribution of unconventional T-cells involved in early infection defence is urgently needed to inform development of vaccines, novel therapies and interventions targeted at this at-risk group.

Methods: We studied immune responses in DM outpatients and healthy controls (non-DM) using whole blood, peripheral blood mononuclear cells and serum from individuals recruited between 2012-2019 in Northeast Thailand. We performed bulk RNA sequencing (n=14-15/group), multiplex protein screening (Mesoscale Discovery platform, n=17-20/group) and 35-color spectral-flow cytometry (n=29-30/group).

Results: We show that individuals with DM have increased myeloid cell activation as well as increased levels of serum proteins involved in TH17 signalling (IL-23, MIP3a), lymph-angiogenesis (VEGF-D), inflammation (LTa, SAA, IL-6, IL-15) and vascular damage (sICAM1). Genes involved in T-cell cytotoxicity were significantly downregulated in individuals with DM compared to those without. On the protein level we found significantly reduced expression of perforin, comparable expression of granzyme B and highly increased levels of granzyme K in CD8+ T-cells, γδ T-cells, MAIT cells, and invariant NK T-cells in DM compared to non-DM. The glucose transporter GLUT-1 was highly upregulated on unconventional T-cells in DM.

Conclusion: We show that people with DM have features of hyper-inflammation with altered cytotoxic features. Further work is assessing the interplay between metabolism and function of cytotoxic T-cells in DM. This will lead to the identification of pathways that can be targeted for interventions.

Biography

Dr. Kronsteiner-Dobramysl is a Senior Immunologist and Deputy Group Head in the lab of Prof. Susanna Dunachie at the University of Oxford with more than 13-years of experience in studying human immune responses to intracellular pathogens including B. pseudomallei and SARS-CoV-2. Her research focuses on understanding how immune competence changes throughout the life-course specifically in the context of underlying chronic inflammatory diseases. Her current work aims to identify targetable pathways responsible for increased susceptibility to infection and impaired immune functioning in the context of diabetes and ageing with a focus on the interplay between metabolism and function.