Loss of balance between protective and proinflammatory synovial tissue T-cell polyfunctionality predates clinical onset of RA

The window for effective therapeutic intervention in rheumatoid Arthritis (RA) is limited. Additionally, current T cell specific therapies for the treatment of RA are broad and affect all T cells irrespective of their contribution to disease pathogenesis and progression, therefore, not differentiating between protective and pathogenic T cell responses. 1-2 More refined and targeted therapeutic approaches will improve disease progression while limiting unwanted side-effects and toxicity. Importantly, characterisation of T cell responses in the synovial tissue of at-risk individuals will help identify prognostic markers and extend the window for effective therapeutic intervention. Ex-Th17 T cells with the capacity to produce multiple pro-inflammatory cytokines simultaneously have previously been identified in the synovial fluid of patients with RA, these polyfunctional T cells are also resistant to inhibition by regulatory T cells (Treg). 3-4

Our understanding of polyfunctional T cells that share characteristics with multiple T cell subsets and transcend previous dogmas of well-defined polarised T cells has increased significantly, however, several key questions remain unanswered. While, the implications of polyfunctional T cell responses extend beyond autoimmunity, response to pathogens, anti-cancer responses and encompass vaccine development, characterisation of polyfunctional T cells is technically challenging and requires new data exploration, visualization and analytical approaches. 5 Polyfunctional CD4 T cells are molecularly distinct from monofunctional cells however, several questions regarding the temporal cytokine production dynamics, transcriptional control and stimulation requirements of polyfunctional T cells remain unanswered. 6 Early studies suggest T cell polyfunctionality is a result of sequential cytokine release with T cells obtaining polyfunctionality status gradually and maintaining simultaneous cytokine secretion for a short period of time. 7 SARS- CoV-2 specific T cell IL-2, TNF-α and IFN-γ cytokine polyfunctionality is dependent on viral antigen specificity and contributes to viral clearance. 8 Importantly, T cell receptor (TCR) dependent and TCR independent stimulation resulted in similar cytokine secretion patterns over time, suggesting that both TCR mediated signals and bystander T cell activation could be important for the emergence of polyfunctional T cell states. 7