Felix Marsh‐Wakefield

Objectives SARS‐CoV‐2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T‐cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T‐cell subsets to disease outcome is imperative to inform the development of next‐generation COVID‐19 vaccines. Methods Immunophenotyping of T‐cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID‐19 clinical presentation. Computational and manual analyses were used to identify T‐cell populations associated with distinct disease states. Results Critical SARS‐CoV‐2 infection was characterised by an increase in activated and cytotoxic CD4 + lymphocytes (CTL). These CD4 + CTLs were largely absent in asymptomatic to severe disease states. In contrast, non‐critical COVID‐19 was associated with high frequencies of naïve T cells and lack of activation marker expression. Conclusion Highly activated and cytotoxic CD4 + T‐cell responses may contribute to cell‐mediated host tissue damage and progression of COVID‐19. Induction of these potentially detrimental T‐cell responses should be considered when developing and implementing effective COVID‐19 control strategies.

Objectives The role of innate lymphoid cells (ILC), particularly helper ILC, in the pathogenesis of multiple sclerosis (MS) is not well understood. Here, we present a comprehensive analysis of peripheral ILC subsets in MS patients prior and after alemtuzumab administration using mass cytometry. Methods Circulating ILC were analysed by mass cytometry in MS patients before and after alemtuzumab. These were compared with non‐MS controls. MS‐related shifts among ILC immunophenotypes were further elucidated by fast interpolation‐based t‐SNE (Flt‐SNE) dimensionality reduction. Results Neither natural killer (NK) cells nor helper ILC (ILC1, ILC2 and ILC3) levels were altered following alemtuzumab treatment. However, CD56 bright NK cell expansions were observed in relapsing patients. MS patients prior to alemtuzumab further displayed proportional shifts from ILC1 to ILC2, with MS‐associated decreases in CCR6 + helper ILC proportions. Conclusion CD56 bright NK cells during relapse indicate an immediate response to disease reactivation, while CCR6‐related shifts among helper ILC suggest altered ILC migration to the CNS during MS.