This application intends to investigate a novel mechanism, by which a newly discovered dendritic cell (DC) of CD8aa + CD11 + phenotype prevents glomerular autoimmune damage by the induction of apoptosis of selfreactive T cells that are causing glomerular damage. Despite their critical role in many autoimmune diseases, pathogenic T cells alone are not sufficient to cause the disease. For example, in our antiGBM glomerulonephritis (GN) model, the disease is induced in WKY rats by a potent nephritogenic T cell epitope pCol(2840) of collagen 4a3 chain. However, LEW rats, which have identical MHC and mount a similar T cell response to pCol(2840), are resistant to GN induction. To define the mechanism associated with GN susceptibility, we first found a transient T cell mediated inflammation in the glomeruli of LEW rats, coincident with infiltration of a novel type of CD8aa + CD11 + DC into the glomeruli. Further studies showed that this glomerular infiltrating DC actively induced a non FasL mediated apoptosis in self reactive T cells through its antigen presentation. In contrast, infiltration of the DC occurred at a much later stage in GN susceptible WKY rats, when glomerular damage had advanced. Therefore, GN resistance in LEW is due to early infiltration of the novel DC which contains further glomerular damage. Our finding reveals a novel self tolerance mechanism for controlling autoimmune diseases after activated T cells initiate tissue damage. This may aid development of new therapeutic strategies for antiGBM GN after its onset. We hypothesize that the novel CD8aa + CD11 + DC is critical for maintenance of self tolerance through its timely infiltration of target tissue and induction of apoptosis of self reactive T cell. In this application, we will fulfill three specific aims to further define this hypothesis. First, we will determine which apoptosis pathway is induced by the DC and whether manipulation of apoptosis would alter GN susceptibility. Second, we will determine whether the DC in WKY is dysfunctional, and whether this is responsible for GN susceptibility. Third, we will test whether glomerular microenvironment is responsible for timely infiltration of the DC.

Public Health Relevance

Anti-GBM glomerulonephritis is a human autoimmune disease that, as of now, is incurable. Using an animal model, we propose to investigate how a special type of dendritic cells control this disease after the tissue damage has begun. With high hopes, our study may aid the development of therapeutic strategies for the disease after its onset.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Flessner, Michael Francis
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University of Texas Health Science Center Houston
Other Basic Sciences
Schools of Dentistry
United States
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Wu, Jean; Carlock, Colin; Ross, April et al. (2016) CD8αα+MHC Class II+ Cell with the Capacity To Terminate Autoimmune Inflammation Is a Novel Antigen-Presenting NK-like Cell in Rats. J Immunol 197:4274-4282
Zhou, Cindy; Lou, Kristie; Tatum, Kiana et al. (2015) Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis. Am J Nephrol 42:42-53
Wu, Jean; Carlock, Colin; Zhou, Cindy et al. (2015) IL-33 is required for disposal of unnecessary cells during ovarian atresia through regulation of autophagy and macrophage migration. J Immunol 194:2140-7
Wu, Jean; Zhou, Cindy; Robertson, Julie et al. (2014) Peripheral blood CD8**(+)CD11c(+)MHC-II(+)CD3(-) cells attenuate autoimmune glomerulonephritis in rats. Kidney Int 85:1078-90
Carlock, Colin I; Wu, Jean; Zhou, Cindy et al. (2014) Unique temporal and spatial expression patterns of IL-33 in ovaries during ovulation and estrous cycle are associated with ovarian tissue homeostasis. J Immunol 193:161-9
Carlock, Colin; Wu, Jean; Zhou, Cindy et al. (2013) Ovarian phagocyte subsets and their distinct tissue distribution patterns. Reproduction 146:491-500
Zhou, Cindy; Robertson, Julie; Wu, Jean et al. (2011) Natural recovery from antiglomerular basement membrane glomerulonephritis is associated with glomeruli-infiltrating CD8ýý+CD11c+MHC class II+ cells. Am J Nephrol 34:519-28
Zhou, Cindy; Wu, Jean; Torres, Lisa et al. (2010) Blockade of osteopontin inhibits glomerular fibrosis in a model of anti-glomerular basement membrane glomerulonephritis. Am J Nephrol 32:324-31
Wu, Jean; Zhou, Cindy; Robertson, Julie et al. (2010) Identification of a bone marrow-derived CD8αα+ dendritic cell-like population in inflamed autoimmune target tissue with capability of inducing T cell apoptosis. J Leukoc Biol 88:849-61
Merszei, Justin; Wu, Jean; Torres, Lisa et al. (2010) Osteopontin overproduction is associated with progression of glomerular fibrosis in a rat model of anti-glomerular basement membrane glomerulonephritis. Am J Nephrol 32:262-71

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