Cell-type- and state-resolved transcriptomics uncovers distinct T cell and monocyte dysregulation in multiple sclerosis

Multiple sclerosis (MS) is a complex immune-mediated disorder involving multiple cell types and genes. Hence, understanding MS calls for cell-type-specific molecular studies to identify dysregulated pathways. In this study, we profile 1,075 transcriptomes from 167 patients with MS and 42 healthy controls across six peripheral immune cell type and states. MS-associated transcriptional differences show up more clearly in unstimulated immune cells than in vitro-stimulated counterparts. We identify co-expressed gene modules including regulators such as ZBTB16, across both T cells and monocytes. The top T cell module is enriched for MS susceptibility genes and affects proliferation.

We made use of a T cell proliferation assay to assess the potential functional effect of our T cell activation-related modules on T cell proliferation rates. For this we used CFSE-staining of PBMC samples from 16 MS patients to 13 healthy controls. These samples were stimulated using anti-CD3/CD28 antibodies, and T cell proliferation rates were quantified using flow cytometry and a Gaussian Mixture model that takes CFSE auto-fluorescence into account. We found a significant association between expression of one of the gene modules prior to stimulation, and higher CD4+ T cell proliferation rates following stimulation. Overall, our data suggest a link between the MS-associated CD4+ T cell modules, a higher T cell activation profile, and higher proliferation rates.

Recommended citation: Roostaei, T. et al (2026). "Cell-type- and state-resolved transcriptomics uncovers distinct T cell and monocyte dysregulation in multiple sclerosis." Cell Reports.
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