Mechanisms of immune homeostasis and regulation of intraocular inflammation

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Several organ-specific autoimmune diseases such as uveitis and multiple sclerosis are mediated by autoreactive CD4+ T cells and are characterized by unpredictable repetitive cycles of explosive inflammatory attacks, which can subside spontaneously (without treatment). Between attacks, there can be little or no evidence of inflammation in the eyes or brain. In this study, we established a long-term mouse model of chronic uveitis and used this model to address the age-old question of where the autoreactive memory T cells that mediate the repeated cycles of remission and recurrent autoimmune disease reside during remissions of inflammation. We induced experimental autoimmune disease (EAU) in mice by immunization with IRBP/CFA and monitored progression of the disease over a period of 6 months by funduscopy, histophathology, optical coherence tomography (OCT) and eletroretinography (ERG). Peak EAU characterized by massive infiltration of Th1/Th17 cells in retina was observed 21 days after disease induction but by day-30 post-immunization the disease went into remission with very few cells detectable in blood or retina. 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, starting 30 to 225 days post-immunization. We show that several months after inception of acute uveitis that residual autoreactive memory T-cells specific to retinal autoantigen, IRBP, relocated to bone marrow (BM). The IRBP-specific memory T-cells (IL-7RαHiLy6CHiCD4+) resided in BM in resting state but upon re-stimulation converted to IL-17-/IFN-γ-expressing effectors (IL-7RαLowLy6CLowCD4+). We further show that recruitment into and retention of IRBP-specific memory T-cells in BM required induction of α4β1 and osteopontin expression by STAT3-dependent mechanism. We adoptively transferred uveitis to nave mice using BM cells from WT mice with chronic uveitis but not with BM cells from IRBP-immunized STAT3-deficient (CD4-STAT3KO) mice. Identifying BM as survival-niche for T-cells that cause uveitis, suggests that BM stromal cells that provide survival signals to autoreactive memory T-cells and STAT3-dependent mechanisms that mediate their relocation into BM, are attractive therapeutic targets that can be exploited to selectively deplete memory T-cells that drive chronic inflammation.