Role of CD5 signalling for pro-inflammatory Th17 response in multiple sclerosis

Pro-inflammatory T-helper 17 (Th17) cells are of vital importance in human autoimmune diseases such as multiple sclerosis (MS). Due to differentiation and functional plasticity, Th17 cells are able to produce a variety of pro-inflammatory cytokines such as interleukin (IL)-17A, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), and modulation of Th17 cell activities represents a desirable tool for disease-modifying treatment. Here, we aimed to understand the role of the surface molecule CD5 and its intracellular interaction partner casein kinase 2 (CK2) in human Th17 effector function as well as their role in multiple sclerosis. We performed targeted single-cell RNA sequencing from CSF obtained from people with multiple sclerosis and non-inflammatory neurological diseases, and high-sensitivity proteomic analysis of serum and CSF from 114 people with multiple sclerosis by using a proximity extension assay (PEA) together with functional investigations on CD4+ memory T cells differentiated into a Th17-polarized phenotype. Blockade of CD5 reduced the production of IL-17A, IFN-γ and GM-CSF by Th17-polarized cells without affecting proliferation. In comparison, blockade of its intracellular interaction partner CK2 exerted partly similar effects with a decrease in IL-17A and GM-CSF production but also impaired T cell proliferation. Both blocking agents resulted in a decreased phosphorylation of the downstream signalling molecule STAT3. The CD5 targeting treatment was able to abolish cytotoxic effects caused by Th17-polarized cells. Importantly, transcriptomic and proteomic analysis showed that CD5 expression correlates with an inflammatory immune profile in multiple sclerosis in serum as well as CSF. Our study highlights the importance of the CD5-CK2-STAT3 signalling axis for inflammatory responses of human Th17-polarized cells. Since in humans CD5 expression correlates with inflammation and cellular injury, targeting the CD5 signalling pathway provides future therapeutic opportunities for-among other diseases-multiple sclerosis.