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Hyun-Mee Oh, Chengrong Yu, YongJun Lee, Chi-Chao Chan, Arvydas Maminishkis, Charles E. Egwuagu; Autoreactive Memory T-cells That Mediate Chronic Uveitis Reside In The Bone Marrow During Disease Remission. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3395.
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The source of autoreactive memory T-cells that initiate and sustain the repeated cycles of remission and recurrent inflammation that characterize most organ-specific autoimmune diseases is largely unknown. In this study, we addressed the age-old question of where autoreactive memory T-cells that mediate chronic uveitis reside in-between episodes of acute inflammation.
We induced experimental autoimmune disease (EAU) in C57BL/6 or B10.A mice by immunization with IRBP/CFA and monitored progression of the disease by funduscopy, optical coherence tomography (OCT), electroretinography (ERG) and histophathology, starting 30 to 225 days post-immunization. We utilized the very sensitive antigen-induced CD154 expression assay to trace the location of autoreactive T cells that persist in peripheral tissues over time.
Our mouse model of chronic uveitis is characterized by progressive photoreceptor-cell loss, retinal-degeneration, focal retinitis, retinal vasculitis, multifocal-choroiditis and choroidal neovascularization, providing for the first time a useful model for studying long-term pathological consequences of chronic inflammation of the neuroretina. Several months after inception of acute uveitis IRBP-specific autoreactive memory T-cells (IL-7RαHiLy6CHiCD4+) T-cells relocated to bone marrow (BM). However, upon re-stimulation they converted to IL-17-/IFN-γ-expressing effectors (IL-7RαLowLy6CLowCD4+) that adoptively transferred uveitis to naïve recipient mice. Interestingly, IRBP-specific STAT3-deficient memory T-cells could not traffic into BM because they are defective in α4β1 activation and osteopontin expression and they could not adoptively transferred uveitis to naïve mice.
We reveal for the first time that autoreactive T cells that initiate acute uveitis subsequently relocate to the BM where they can persist there for a long time as resting memory cells. However, upon encounter with cognate autoantigen they convert to potentially pathogenic effector T cells that may fuel subsequent cycles of recurrent uveitis. Furthermore, we have shown that relocation of the IRBP-specific autoreactive memory T cells to BM is dependent in part on STAT3 pathways. Thus, new therapeutic strategies targeting IL-7RαHiLy6CHiCD4+ memory T-cells, IL-7-secreting BM stromal cells or STAT3-dependent mechanisms may be viable alternative to conventional therapy for uveitis.
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