In:
The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 218.10-218.10
Abstract:
Autoimmune uveitis, a major cause of blindness, is thought to be driven by T cells specific for unique retinal antigens that have been activated and acquired the ability to cross the blood-retinal barrier. However, it is unknown where and how they first become activated. The R161H mouse expresses a transgenic TCR specific for the retinal protein IRBP and develops spontaneous uveitis with 100% incidence, permitting to study natural triggers of disease. Retina-specific T cells were activated in the intestine of specific-pathogen-free (SPF) R161H mice. Elimination of gut commensals by oral treatment with antibiotics (ABX) or by rearing under germ-free conditions (GF) significantly attenuated uveitis and reduced Th17 cells in the gut lamina propria. Bacteria-rich extracts of intestinal contents from SPF, but not GF or ABX mice, activated retina-specific T cells in vitro, and R161H T cells signaled through the clonotypic TCR in the gut in vivo, suggesting a role for gut microbiota as a source of stimulating signals for retina-specific T cells. To dissect the contribution of adaptive vs innate microbial signals, gnotobiotic studies were performed: GF R161H mice exposed to SPF conditions developed full-blown uveitis, but mono-colonization with segmented filamentous bacteria (SFB) or a Turicibacter strain (T. H121) only partially restored disease. Unlike intestinal extracts from SPF mice, extracts from monocolonized mice failed to activate R161H T cells in vitro, suggesting lack of “antigen” activity, but SFB (not T. H121) restored gut Th17-producing cells, indicating presence of “adjuvant” activity. Thus, microbial-derived adaptive “antigen” and innate “adjuvant” signals are both required for full development of uveitis.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.198.Supp.218.10
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2017
detail.hit.zdb_id:
1475085-5
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