Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells

Zhou, Cindy; Robertson, Julie M.; Wu, Jean; Bartkowiak, Todd; Parker, Kevin; McMahon, John; Lou, Yahuan

doi:10.1159/000333004

Cited by 3 publications

(16 citation statements)

References 60 publications

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“…Similar to those in the immunized WKY rats, the largest population was CD11 + phagocyte, followed by CD4 + CD3 + T cell with CD8 + CD3 + T cell the smallest (fig. 4a, b) [21]. Relative sizes of the above three populations were comparable to those in WKY rats at day 35 (fig.…”

Section: Resultsmentioning

confidence: 79%

“…inflammation peak). Previous analyses on GILs in immunized WKY rats have detected four populations: 1) CD4 + T cell, 2) CD8 + T cell, 3) CD11 + macrophage, and 4) CD11 + CD8 + cell [19, 21]. Three immunized LEW WKY rats with severe albuminuria (4000mg/dl) were selected for isolation of GILs at day 35.…”

Section: Resultsmentioning

confidence: 99%

“…As expected, flow cytometry did not detect any sizable GIL populations in WKY rats at day 45 due to replacement of inflammation by severe fibrosis (fig. 4a, c) [20, 21]. …”

Section: Resultsmentioning

confidence: 99%

“…For flow cytometry of GIL populations, stained cells were first gated on FSC vs SCC plot to enrich leukocyte population. Relative size of each population was calculated as percentage of total gated cells [20, 21]. For depletion or isolation of a certain cell population, magnetic bead-conjugated antibodies were used on a cell sorter (AutoMACS Pro Separator, Miltenyi Biotec, Germany) [19].…”

Section: Methodsmentioning

confidence: 99%

“…Antigen-presenting cells (APC) of LEW rats can effectively present antigens to T cells of WKY rats, and vice versa [20]. However, LEW rats are GN-resistant [19–21]. In this study, BM chimeras between WKY and LEW were created to determine which cells or tissues were responsible for each phase.…”

Section: Introductionmentioning

confidence: 99%

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Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis

Zhou¹,

Lou

Tatum³

et al. 2015

Am J Nephrol

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Background: Many types of glomerulonephritis (GN) undergo tandem connected phases: inflammation and fibrosis. Fibrosis in human GNs leads to irreversible end-stage disease. This study investigated how these 2 phases were controlled. Methods: Using a rat anti-glomerular basement membrane GN model, we established bone marrow (BM) chimeras between GN-resistant Lewis (LEW) and GN-susceptible Wistar Kyoto (WKY) rats. Glomerular inflammation and fibrosis were compared between chimeras. Results: LEW's BM to WKY chimeras with or without co-transfer of host WKY's T cells were GN-resistant. On the other hand, WKY's BM to LEW (LEW^WKY) chimeras developed glomerular inflammation and albuminuria upon immunization. Quantitative analysis showed that the number and composition of inflammatory cells in glomeruli of immunized LEW^WKY chimeras were similar to those in immunized WKY rats at their inflammatory peak. Thus, glomerular inflammation was controlled by BM-derived non-T cell populations. However, unlike WKY rats, LEW^WKY rats did not develop fibrosis until the end of experiments (84 days) in spite of persistent inflammation and albuminuria. Conclusion: Inflammation alone was not sufficient to trigger fibrosis, suggesting a critical role of glomerular cells in the fibrotic process. As LEW^WKY chimera allows us to separate glomerular inflammation from fibrosis, this model provides a useful tool to study how fibrosis is initiated following inflammation.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

“…As expected, flow cytometry did not detect any sizable GIL populations in WKY rats at day 45 due to replacement of inflammation by severe fibrosis (fig. 4a, c) [20, 21]. …”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis

Zhou¹,

Lou

Tatum³

et al. 2015

Am J Nephrol

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Peripheral blood CD8αα + CD11c + MHC-II + CD3 - cells attenuate autoimmune glomerulonephritis in rats

Zhou

Robertson

et al. 2014

Kidney International

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In an anti-GBM glomerulonephritis (GN) model, GN-resistant Lewis rats naturally recover from early glomerular inflammation. Here we investigated recovery mechanisms for development of a potential immunotherapy for autoimmune GN. Our previous studies suggested that glomeruli-infiltrating leukocytes with a phenotype of CD8αα+CD11c+MHC−II+CD3− (GIL CD8αα+ cells) were responsible for recovery through induction of T cell apoptosis. Now, we identified peripheral blood CD8αα+CD11c+MHC−II+CD3− cells (PBMC CD8αα+CD3− cells), which shared 9 markers with GIL CD8αα+ cells. Upon incubation, PBMC CD8αα+CD3− cells displayed a morphology resembling that of dendritic cells. Similar to GIL CD8αα+ cells, PBMC CD8αα+CD3− cells were capable of inducing T cell apoptosis in vitro. Hence, PBMC CD8αα+CD3− cells were likely the precursor of GIL CD8αα+ cells. We next tested their potential in vivo function. PBMC CD8αα+CD3− cells were able to infiltrate inflamed but not normal glomeruli. Isolated PBMC CD8αα+CD3− cells of Lewis rats were transferred into GN-prone Wistar Kyoto rats at early inflammatory stage (day 17–25). When examined at day 45, both histopathology and BUN/serum creatinine level showed significantly attenuated GN in 80% of cell recipient Wistar Kyoto rats. Separate experiments verified infiltration of transferred Lewis PBMC CD8αα+CD3− into the glomeruli, accompanied with apoptotic CD4+ T cells in the glomeruli of the recipient Wistar Kyoto rats. Thus, PBMC CD8αα+CD3− cells of Lewis rats were able to terminate ongoing autoimmune inflammation in the glomeruli.

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CD8αα+MHC Class II+ Cell with the Capacity To Terminate Autoimmune Inflammation Is a Novel Antigen-Presenting NK-like Cell in Rats

Carlock

Ross

et al. 2016

The Journal of Immunology

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Discovery of immune tolerance mechanisms, which inhibit pre-existing autoimmune inflammation, may provide us with new strategies for treating autoimmune diseases. We have identified a CD8αα+MHC-II+ cell with professional APC capacity during our investigation on spontaneous recovery from autoimmune glomerulonephritis in a rat model. This cell actively invades inflamed target tissue and further terminates an on-going autoimmune inflammation by selective killing of effector autoreactive T cells. Now, we showed that this cell used a cytotoxic machinery of Ly49s+ NK cells in killing of target T cells. Thus, this CD8αα+MHC-II+ cell was a dually functional antigen presenting NK-like (AP-NK) cell. Following its coupling with target T cells through antigen presentation, killing stimulatory receptor Ly49s6 and co-receptor CD8αα on this cell used non-classic MHC-I RT1CE16 on the target T cells as a ligand to initiate killing. Thus, activated effector T cells with elevated expression of RT1CE16 were highly susceptible to the killing by the CD8αα+ AP-NK cell. Granule cytolytic perforin/granzyme C from this cell subsequently mediated cytotoxicity. Thus, inhibition of granzyme C effectively attenuated the killing. As it can recognize and eliminate effector autoreactive T cells in the inflamed target tissue, CD8αα+ AP-NK cell not only represents a new type of immune cell involved in immune tolerance, but also is a potential candidate for developing a cell-based therapy for pre-existing autoimmune diseases.

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Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells

Cited by 3 publications

References 60 publications

Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis

Differentiating Glomerular Inflammation from Fibrosis in a Bone Marrow Chimera for Rat Anti-Glomerular Basement Membrane Glomerulonephritis

Peripheral blood CD8αα + CD11c + MHC-II + CD3 - cells attenuate autoimmune glomerulonephritis in rats

CD8αα+MHC Class II+ Cell with the Capacity To Terminate Autoimmune Inflammation Is a Novel Antigen-Presenting NK-like Cell in Rats

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