Role of skin-based T cell immunity in acute dengue infection

Abstract

Dengue is an endemic disease in Singapore, where epidemic waves are observed every few years. DENV is transmitted via the Aedes mosquito bite on the human skin. Circulating dengue- specific T cells expressing the Cutaneous Lymphocyte-Associated Antigen (CLA) marker home to the skin, where they potentially become tissue-resident memory T (T_RM) cells. In other viral infections, T_RM cells are critical for immune protection but their role in dengue remains unknown. This project aims to understand the role of T cells in acute dengue by 1) investigating the differences between T cells in the skin and peripheral blood, 2) comparing perturbations of these T cells in dengue-infected patients against healthy volunteers and 3) comparing the correlations of T cell immunity with clinical manifestations. Flow cytometry was used to investigate the phenotype and relationship of total CD4+ and CD8+ T cells derived from peripheral blood and skin-suction blisters of acute dengue patients and healthy volunteers in Singapore. Results from Uniform Manifold Approximation and Projection (UMAP) and clustering algorithm PhenoGraph show that skin and blood T-cell populations are largely distinct from one another. The CD4+ and CD8+ T cells in the skin of acute dengue patients are more activated and proliferating (CD38+HLA-DR+, Ki-67+, PD-1+) and display increased cytotoxic potential (Granzyme B+) compared to their blood counterparts. They also express markers of tissue residency CD69 +/- CD103, which suggests that they belong to the T_RM lineage. Furthermore, analysis comparing the skin T cells in dengue patients with different clinical manifestations show that Granzyme B and PD-1 correlate with better protection against thrombocytopenia. This study of the features of cell populations in blood versus skin in acute infections may give us insights into the role of dengue-specific T-cells and T_RM cells for immune protection and/or immunopathology.

Date of Award	20 Jun 2023
Original language	English
Awarding Institution	University of Bristol
Supervisor	Laura Rivino (Supervisor)