Circulating follicular helper T cells exhibit reduced ICOS expression and impaired function in narcolepsy type 1...

Despite genetic and epidemiological evidence strongly supporting an autoimmune basis for narcolepsy type 1, the mechanisms involved have remained largely unknown. Here, we aimed to investigate whether the frequency and function of circulating follicular helper and follicular regulatory T cells are altered in narcolepsy type 1. Peripheral blood mononuclear cells were collected from 32 patients with narcolepsy type 1, including 11 who developed disease after Pandemrix^® vaccination, and 32 age-, sex-, and HLA-DQB1*06:02-matched healthy individuals. The frequency and phenotype of the different circulating B cell and follicular T cell subsets were examined by flow cytometry. The function of follicular helper T cells was evaluated by assessing the differentiation of naïve and memory B cells in a co-culture assay. We revealed a notable increase in the frequency of circulating B cells and CD4⁺CXCR5⁺ follicular T cells in narcolepsy patients compared to age-, sex- and HLA-matched healthy controls. However, the inducible T-cell costimulator molecule, ICOS, was selectively down-regulated on follicular T cells from patients. Reduced frequency of activated ICOS⁺ and PD1^high blood follicular T cells was also observed in the narcolepsy group. Importantly, follicular T cells isolated from patients with narcolepsy type 1 had a reduced capacity to drive the proliferation/survival and differentiation of memory B cells. Our results provide novel insights into the potential involvement of T cell-dependent B cell responses in the pathogenesis of narcolepsy type 1 in which down-regulation of ICOS expression on follicular helper T cells correlates with their reduced function. We hypothesize that these changes contribute to regulation of the deleterious autoimmune process after disease onset.