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bioRxiv · 10.1101/2021.11.16.468816

Whole transcriptome-sequencing and network analysis of CD1c+ human dendritic cells identifies cytokine-secreting subsets linked to type I IFN-negative autoimmunity to the eye

Hiddingh, S.·Pandit, A.·Verhagen, F.·Rijken, R.·Servaas, N.·Komer-Wichers, R.·Dam-van Loon, N. t.·Imhof, S. S.·Radstake, T.·de Boer, J. H.·Kuiper, J. J. W.
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Abstract

BackgroundType I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear. MethodsWe analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations. ResultsWe report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed towards a gene module with the chemokine receptor CX3CR1 as the key hub gene. We confirmed these results in an independent case-control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1-DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3-like cells can be detected in inflamed eyes of patients. ConclusionsThese results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. FundingThe presented work is supported by UitZicht (project number #2014-4, #2019-10, an #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.

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Hiddingh, S., Pandit, A., Verhagen, F., Rijken, R., Servaas, N., Komer-Wichers, R., Dam-van Loon, N. t., Imhof, S. S., Radstake, T., de Boer, J. H., Kuiper, J. J. W.. 2021-11-19. Whole transcriptome-sequencing and network analysis of CD1c+ human dendritic cells identifies cytokine-secreting subsets linked to type I IFN-negative autoimmunity to the eye. https://doi.org/10.1101/2021.11.16.468816

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