Autoreactive Memory CD4+ T Lymphocytes That Mediate Chronic Uveitis Reside in the Bone Marrow through STAT3-Dependent Mechanisms

  • Oh H
  • Yu C
  • Lee Y
  • et al.
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Abstract

Organ-specific autoimmune diseases are usually characterized by repeated cycles of remission and recurrent inflammation. However, where the autoreactive memory T cells reside in between episodes of recurrent inflammation is largely unknown. In this study, we have established a mouse model of chronic uveitis characterized by progressive photoreceptor cell loss, retinal degeneration, focal retinitis, retinal vasculitis, multifocal choroiditis, and choroidal neovascularization, providing for the first time to our knowledge a useful model for studying long-term pathological consequences of chronic inflammation of the neuroretina. We show that several months after inception of acute uveitis, autoreactive memory T cells specific to retinal autoantigen, interphotoreceptor retinoid-binding protein (IRBP), relocated to bone marrow (BM). The IRBP-specific memory T cells (IL-7RαHighLy6CHighCD4+) resided in BM in resting state but upon restimulation converted to IL-17/IFN-γ–expressing effectors (IL-7RαLowLy6CLowCD4+) that mediated uveitis. We further show that T cells from STAT3-deficient (CD4-STAT3KO) mice are defective in α4β1 and osteopontin expression, defects that correlated with inability of IRBP-specific memory CD4-STAT3KO T cells to traffic into BM. We adoptively transferred uveitis to naive mice using BM cells from wild-type mice with chronic uveitis but not BM cells from CD4-STAT3KO, providing direct evidence that memory T cells that mediate uveitis reside in BM and that STAT3-dependent mechanism may be required for migration into and retention of memory T cells in BM. Identifying BM as a 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.

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APA

Oh, H.-M., Yu, C.-R., Lee, Y., Chan, C.-C., Maminishkis, A., & Egwuagu, C. E. (2011). Autoreactive Memory CD4+ T Lymphocytes That Mediate Chronic Uveitis Reside in the Bone Marrow through STAT3-Dependent Mechanisms. The Journal of Immunology, 187(6), 3338–3346. https://doi.org/10.4049/jimmunol.1004019

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