High Dimensional Profiling of T cells in ME/CFS Uncovers Sex Specific Dysregulation 2309017

Abstract Introduction Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a debilitating and poorly understood chronic disease. ME affects more women than men and studies have shown sex differences in disease presentation. Patients experience symptoms indicative of immune dysregulation including sore throat and tender lymph nodes. Transcriptomic and functional analyses have identified T cell dysfunction in ME (Vu et al 2024; Gil A et al 2024; Visser et al 1998). ME T cell research has largely been done on bulk lineage populations and fails to discriminate dysregulation within different functional or differentiation states. Analysis has often combined data from both sexes, even though sex differences in immune response could mask sex-specific disease presentation. Given the complexity and importance of the T cell compartment and the role sex plays in immune function, it is critical to rigorously identify sex and subset-specific dysregulation in ME. Methods Cytometry by Time of Flight identifies cell surface protein expression at the single cell level. We used a panel tailored to T cells to characterize peripheral blood mononuclear cells from 53 ME patients (11 M and 42 F) and 36 (10 M and 26 F) healthy controls and identified cell types using unsupervised clustering. Results Only in ME males is there an increase in the percent of CD27+ γδ T cells, which produce IFNγ. IFNγ targets intracellular pathogens and the increase could implicate an increased response to viral pathogens in ME. Female ME CD8+ T cells show a chronically stimulated phenotype across T memory subsets, while male ME memory cells show a subset specific activation phenotype. Conclusion This work identifies functionally relevant changes in T cell subsets in ME and highlights the importance of examining sex differences when studying chronic disease. Understanding T cell dysfunction in ME on a sex and subtype level will aid in determining the mechanism of immune dysfunction and reveal potential therapeutic targets. Funding Source NIH NIAID U54AI178855 Topic Categories Translational and Interventional Immunology (TI)