Peripheral T helper CD4⁺ cells mediate autoimmunity in Aire-deficient model of chronic inflammatory demyelinating polyneuropathy

Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) occurs spontaneously in NOD mice with Aire deficiency (NOD.Aire GW/+). The disease is mainly driven by CD4 +cells. However, the contribution of different CD4 +T cell subsets to the pathogenicity of neuropathy is not well studied. Results: scRNA-seq of the immune cells infiltrating the sciatic nerves show that the majority of the CD4 +cells express genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cells, a newly described T helper type. Tph cells are similar to Tfh cells as they have prominent expression of ICOS, PD1, and IL-21. These IL-21 +Tph cells are also IFN-γ, IL-10 and CXCR6 positive, suggesting an effector phenotype. We verified high levels of IL-21 expression in Tfh and Tph cells in spleen and nerves by flow cytometry using IL-21 reporter mice. Transfer of CD4 +IL-21 +cells from NOD.Aire GW/+donor mice to immunodeficient mice resulted in higher neuropathy incidence than transfer of CD4 +IL21 −cells. In adoptive transfer model, inhibition of Tfh specific transcription factor BCL6 decreased the frequency of Tfh and Tph cells in the peripheral nerves and protected against neuropathy development. Conclusion: IL-21 producing Tfh and Tph cells may play a major pathogenic role in neuropathy development and suggests new therapeutic targets for CIDP. Supported by grants from NIH