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Th1 effector CD4+ cells contribute to the pathogenesis of proliferative and crescentic glomerulonephritis, but whether effector Th17 cells also contribute is unknown. We compared the involvement of Th1 and Th17 cells in a mouse model of antigen-specific glomerulonephritis in which effector CD4+ cells are the only components of adaptive immunity that induce injury. We planted the antigen ovalbumin on the glomerular basement membrane of Rag1(-/-) mice using an ovalbumin-conjugated non-nephritogenic IgG1 monoclonal antibody against alpha3(IV) collagen. Subsequent injection of either Th1- or Th17-polarized ovalbumin-specific CD4+ effector cells induced proliferative glomerulonephritis. Mice injected with Th1 cells developed progressive albuminuria over 21 d, histologic injury including 5.5 +/- 0.9% crescent formation/segmental necrosis, elevated urinary nitrate, and increased renal NOS2, CCL2, and CCL5 mRNA. Mice injected with Th17 cells developed albuminuria by 3 d; compared with Th1-injected mice, their glomeruli contained more neutrophils and greater expression of renal CXCL1 mRNA. In conclusion, Th1 and Th17 effector cells can induce glomerular injury. Understanding how these two subsets mediate proliferative forms of glomerulonephritis may lead to targeted therapies.

Dendritic cells in the kidney take up antigens, but little is known about their role in providing co-stimulatory signals for the activation of CD4(+) cells. This study examined the phenotype of dendritic cells in the renal interstitium and in the lymph node draining the kidney before and after intrarenal ovalbumin injection. After intrarenal injection of the antigen, expression of the co-stimulatory molecules CD86 and programmed cell death ligand 1 (PD-L1) increased on renal dendritic cells, whereas expression of only CD86 increased on dendritic cells of the draining lymph node. The activation and proliferation of antigen-specific CD4(+) cells in the lymph node were assessed by transfer of naïve, fluorescently labeled ovalbumin-specific T cell receptor transgenic cells to mice before antigen administration. Blocking both CD86 and CD80 profoundly inhibited CD4(+) cell proliferation, but CD86 was the dominant CD28 ligand in the early proliferative response of CD4(+) cells. Conversely, activation of PD-1, the receptor expressed on CD4(+) cells that binds PD-L1 and PD-L2, reduced the proliferation of CD4(+) cells in the draining lymph node. Comparing subcutaneous and intrarenal administration of antigen, it was found that CD4(+) cell activation was slower and the effects of combined CD80 and CD86 blockade were more profound when antigen was presented via the kidney compared with the skin. In summary, renal dendritic cells take up antigen and participate in the control of antigen-specific CD4(+) cell proliferation by upregulating co-stimulatory molecules such as CD86 that stimulate CD4(+) cell proliferation and by signaling through PD-1, which prevents an inappropriately exuberant immune response.

Minimal-change disease (MCD) and primary FSGS are important causes of idiopathic nephrotic syndrome (INS) and, in the case of FSGS, end-stage renal failure. Intriguing features of these diseases include their frequent response to steroids, their association with immune abnormalities, the existence