TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model

Pearson, James Alexander ORCID: https://orcid.org/0000-0002-2867-2269, Hu, Youjia, Peng, Jian, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Wen, Li 2024. TLR5-deficiency controls dendritic cell subset development in an autoimmune diabetes-susceptible model. Frontiers in Immunology 15 , 1333967. 10.3389/fimmu.2024.1333967

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Abstract

Introduction: The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D. Methods: To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study. Results: We found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice. Discussion: In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	Frontiers Media
ISSN:	1664-3224
Funders:	MRC
Date of First Compliant Deposit:	8 March 2024
Date of Acceptance:	6 February 2024
Last Modified:	16 Apr 2024 09:07
URI:	https://orca.cardiff.ac.uk/id/eprint/167008

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