Ralph, Elizabeth Ona Louise; (2025) Characterisation of CD161+ T cells in childhood arthritis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Juvenile Idiopathic Arthritis (JIA) is the most common childhood autoimmune rheumatic disorder. Pathogenesis of the condition remains unclear and is likely multi-factorial. CD161+ CD4 T cells producing pro-inflammatory cytokines observed at the disease site are therefore of interest. Using a large single-cell RNAseq dataset of immune cells in the synovial fluid (SF) generated for this thesis, I identified transcriptional differences between KLRB1+ (the gene encoding CD161) and KLRB1- regulatory T cells (Treg), and observed that several genes associated with T peripheral helper (Tph) cells were upregulated in KLRB1+ Treg. I confirmed this finding in SF and synovial tissue cells in a second independent dataset (MAP-JAG). These differentially expressed genes and a set of canonical Tph genes were found to be expressed in particular sub-clusters of KLRB1+ and KLRB1- Treg, and this finding was confirmed in the total Treg population in the MAP-JAG dataset. Additionally, there was notable overlap in the TCR repertoires of these sub-clusters (‘Tph-like Treg’) and the Tph cluster, particularly for KLRB1+ Tph-like Treg, suggesting that these cells may be related. Pilot experiments to identify Tph-like Tregs at a cellular level showed a small population of Tregs with potential Tph-like features though this could not be conclusively confirmed. This work provides a foundation for further research into the nature of Tph-like Treg, and their implication for the treatment of children with JIA. Finally, I confirmed previous observations of an enrichment of CD161+ and cytokine-producing CD161+ T cells in SF. There were limited associations between these cells and disease activity at the time of sample pre-treatment. However, regression modelling using CD161+ T cell measures and changes in disease outcome measures after treatment showed some associations. This provides a rationale for further investigation of the use of CD161+ T cells as a predictor of treatment response.

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