Mechanisms of T cell mediated kidney disease

Abstract

Immune mediated glomerulonephritis (GN) is a major cause renal inflammation leading to terminal kidney failure. B cells and autoantibodies are well known to contribute to the progression of glomerular disease. The role of CD8⁺ T cells, however, remains to be clarified, partially because of lack of suitable disease models.<br /> To investigate this question, a transgenic murine model system was created by expressing a membrane-bound model antigen (OVA-HEL) under the control of the nephrin promoter specifically on glomerular podocytes (NOH mice). These cells would then be targets of adoptively transferred OVA- or HEL-specific lymphocytes. NOH mice could therefore be used as a model for antigen specific attacks of the cellular or humoral immune response. This approach has been used successfully in the past to elucidate mechanisms in other autoimmune diseases, e.g. Diabetes Type I and Autoimmune Encephalomyelitis.<br /> CD8⁺ OVA-specific T cells were activated exclusively in the renal draining lymph node in a DC dependent fashion, indicating cross-presentation of glomerular antigen whereas CD4⁺ OVA-specific T cells remained inactive after adoptive transfer.<br /> In contrast to the Diabetes models, even high numbers of OVA-specific CD8⁺ T cells alone only inflicted minor glomerular damage. Co-injection of OVA-activated OVAspecific CD4⁺ T helper cells induced influx of antigen specific T cells and inflammatory mononuclear cells and resulted in renal immunopathology. The infiltrate was predominantly periglomerular, similar to the histological changes seen in rapid progressive forms of glomerulonephritis. The infiltrate was dominated by myeloid dendritic cells (DC) expressing CD11c, CD11b and the costimulatory markers CD40 and CD86, proinflammatory DC of the Gr-1^hiCX3CR1^lo phenotype and also contained antigen-specific CD8⁺ and CD4⁺ T cells. DC activation and CD8⁺ T cell effector function strongly depended on the availability of CD4⁺ T cell help. Persisting infiltration led to podocyte dysfunction and glomerulosclerosis. CD8⁺ T cell priming in the kidney lymph node as well as inflammation within the kidney required the presence of DCs, as demonstrated by ablation of CD11c⁺ cells in NOH x CD11c-diphteria toxin receptor mice, which allow deletion of DCs upon injection of diphtheria toxin. Within infiltrates, proinflammatory cytokines and the chemokines CCL2, 3, 4 and 5 as well as their correlating receptors were detected on infiltrating leukocytes.<br /> These findings demonstrate that T cells specific for glomerular antigens can induce kidney immunopathology and structural damage reminiscent of rapid and crescentic types of glomerulonephritis.