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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
U.S. National Eye Institute
Zip Code
Yu, Cheng-Rong; Choi, Jin Kyeong; Uche, Anita N et al. (2018) Production of IL-35 by Bregs is mediated through binding of BATF-IRF-4-IRF-8 complex to il12a and ebi3 promoter elements. J Leukoc Biol 104:1147-1157
He, Chang; Yu, Cheng-Rong; Mattapallil, Mary J et al. (2016) SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis). Mediators Inflamm 2016:2939370
Wang, Xiaoqian; Wei, Yinxiang; Xiao, He et al. (2016) Pre-existing CD19-independent GL7(-) Breg cells are expanded during inflammation and in mice with lupus-like disease. Mol Immunol 71:54-63
Wan, Chi-Keung; He, Chang; Sun, Lin et al. (2016) Cutting Edge: IL-1 Receptor Signaling is Critical for the Development of Autoimmune Uveitis. J Immunol 196:543-6
Wang, Xiaoqian; Wei, Yinxiang; Xiao, He et al. (2016) A novel IL-23p19/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice. Eur J Immunol 46:1343-50
Sun, Lin; St Leger, Anthony J; Yu, Cheng-Rong et al. (2016) Interferon Regulator Factor 8 (IRF8) Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells. PLoS One 11:e0155420
Egwuagu, C E; Sun, L; Kim, S-H et al. (2015) Ocular Inflammatory Diseases: Molecular Pathogenesis and Immunotherapy. Curr Mol Med 15:517-28
He, Chang; Yu, Cheng-Rong; Sun, Lin et al. (2015) Topical administration of a suppressor of cytokine signaling-1 (SOCS1) mimetic peptide inhibits ocular inflammation and mitigates ocular pathology during mouse uveitis. J Autoimmun 62:31-8
Yu, Cheng-Rong; Hayashi, Kozaburo; Lee, Yun Sang et al. (2015) Suppressor of cytokine signaling 1 (SOCS1) mitigates anterior uveitis and confers protection against ocular HSV-1 infection. Inflammation 38:555-65
Kim, Sung-Hye; Burton, Jenna; Yu, Cheng-Rong et al. (2015) Dual Function of the IRF8 Transcription Factor in Autoimmune Uveitis: Loss of IRF8 in T Cells Exacerbates Uveitis, Whereas Irf8 Deletion in the Retina Confers Protection. J Immunol 195:1480-8

Showing the most recent 10 out of 25 publications