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Crescentic glomerulonephritis in CD4- and CD8-deficient mice. Requirement for CD4 but not CD8 cells
1Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia. peter.tipping@med.monash.edu.au
Insights
CD4 T-cells are essential for developing crescentic glomerulonephritis (GN) in mice. However, the absence of CD8 T-cells accelerates this kidney disease, suggesting a complex immune role.
Area of Science:
- Immunology
- Nephrology
- Pathology
Background:
- Crescentic glomerulonephritis (GN) is a severe kidney disease characterized by rapid glomerular damage.
- The roles of specific T-cell subsets, CD4 and CD8, in GN pathogenesis are not fully elucidated.
Purpose of the Study:
- To investigate the distinct contributions of CD4 and CD8 T-cells to the development of experimental crescentic GN in mice.
- To determine if T-cell deficiencies influence disease severity and progression.
Main Methods:
- Utilized genetically modified mice lacking CD4 cells, CD8 cells, or both (CD4/CD8 deficient).
- Induced GN using sheep anti-mouse glomerular basement membrane globulin.
- Assessed glomerular injury, crescent formation, azotemia, and proteinuria at various time points.
Main Results:
- Wild-type mice developed progressive GN with significant crescent formation, azotemia, and proteinuria by day 21.
- CD4-deficient and CD4/CD8-deficient mice showed minimal GN, with absent crescents, azotemia, and proteinuria.
- CD8-deficient mice exhibited accelerated and severe crescentic GN, with increased mortality.
Conclusions:
- CD4 T-cells are critical mediators for the development of crescentic GN in this mouse model.
- The absence of CD8 T-cells exacerbates crescentic GN, indicating a regulatory or protective role.
- These findings support a model where crescent formation in GN is driven by CD4-dependent delayed-type hypersensitivity.
Abstract:
The contribution of CD4 and CD8 cells to crescentic glomerulonephritis (GN) was studied in mice genetically deficient in CD4, CD8, and with combined CD4 and CD8 (CD4/CD8) deficiency. Wild-type (C57BL/6) mice developed GN with mild proliferative changes 7 days after an intravenous dose of sheep anti-mouse glomerular basement membrane globulin. Crescents were observed in 12.5 +/- 6.1% of glomeruli on day 14. On day 21, 51.5 +/- 7.3% of glomeruli were affected by crescents, and mice had marked azotemia and proteinuria. CD4 and combined CD4/CD8-deficient mice developed minimal evidence of GN. On day 21, their glomeruli showed only mild proliferative changes and crescents, azotemia, and proteinuria were absent. In contrast, CD8-deficient mice developed severe crescentic GN with three of five mice dying on day 20 with ascites and edema. The two mice surviving to day 21 had severe azotemia. Crescent development was accelerated (day 14, 51.6 +/- 2.4% of glomeruli; day 20 or 21, 62.0 +/- 4.0% of glomeruli). These studies demonstrate that CD4 cells are crucial for the development of crescentic GN in mice and that genetic absence of CD8 cells accelerates disease. They support the hypothesis that crescent formation is a manifestation of CD4-dependent (and CD8-independent) delayed type hypersensitivity in the glomerulus.
