Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: autoimmune disease • uveitis-clinical/animal model • memory