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Thesis Defense — High-dimensional analysis of the systemic and microenvironmental immunomes in enthesitis-related arthritis reveals a potentially pathogenic CXCR3+CCR6+ CD4+ T cell subset


Enthesitis-related arthritis (ERA), a common subtype of juvenile idiopathic arthritis (JIA), carries a poor prognosis. We hypothesised that potentially pathogenic immune cell subsets communicate between the circulatory and synovial compartments of ERA patients, where the joint microenvironment facilitates chemoattraction and activation of these subsets to cause inflammation. We first interrogated, via mass cytometry, the systemic immunomes of active ERA patients and healthy paediatric controls. The ERA systemic immunome is structurally and functionally similar to healthy blood, except for an expanded CXCR3+CCR6+CD4+ effector T cell (Teff) population. We then compared the ERA systemic and microenvironmental immunomes, which revealed synovial Th1 and Th17 expansion. Importantly, CXCR3+CCR6+CD4+ Teffs may migrate along a pathogenic chemokine gradient into the synovium, where they accumulate and activate. Single-cell ATAC-seq uncovered high CXCR3 and CCR6 accessibility in synovial CD4+ T cells, including those committed to Th1 and Th17 pathways. In-vitro, CXCR3+CCR6+CD4+ Teffs differentiate into Th1 and Th17 cells following TCR activation. Although CXCR3+CCR6+ CD4+ regulatory T cells (Tregs) also accumulate in the joint and were shown in-vitro to be bona fide Tregs, they may not be sufficiently expanded in the microenvironment. Elucidating the interdependence of CXCR3+CCR6+CD4+ T cells, the associated chemokine gradient, and Th1 and Th17 effectors may refine ERA therapy.









Date and Time

23 Mar 2023 @ 09:00 - 23 Mar 2023 @ 10:00


Tay Shi Huan



Duke-NUS Medical School, Amphitheatre, Level 2 (No registration required)