Plasticity and heterogeneity of Th17 in immune-mediated kidney diseases.

Anti-neutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis, anti-glomerular basement membrane (GBM) glomerulonephritis and lupus nephritis are the most common causes of rapid progressive glomerulonephritis (RPGN) in the Western world. These aggressive forms of autoimmune kidney diseases significantly contribute to end-stage renal disease and are associated with high morbidity and mortality. Moreover, patients show significant heterogeneity with respect to clinical outcome and response to therapy. T cell infiltration is a morphological hallmark of RPGN and it is a critical driver of kidney injury. Different CD4+ T cell subsets that are endowed with distinct regulatory and effector functions are involved in this detrimental inflammatory process. In particular, the identification and functional characterization of IL-17-expressing CD4+ Th17 cells have substantially advanced our understanding of organ-specific autoimmunity. In experimental models of crescentic and proliferative GN, including ANCA-associated GN, anti-GBM-GN and lupus nephritis, the Th17/IL-17 axis significantly contributes to renal tissue damage. In patients with ANCA-associated GN or lupus nephritis, IL-17 serum levels correlated with disease activity. Moreover, Th17 cells are present in the kidneys of these patients and represents a topic of intense ongoing clinical and basic research. Importantly, recent studies have challenged the view of CD4+ T cells subsets as terminally differentiated homogenous cells, showing that T cells, in particular Th17 cells, are much more flexible and heterogeneous than previously thought. However, analysis of Th17 cell fate in mouse models of autoimmune kidney disease revealed a high degree of stability within these cells, an observation that is in contrast to Th17 cells in other models of autoimmune diseases including experimental autoimmune encephalomyelitis. Interestingly, anti-CD3 treatment interferes with stable Th17 cells and induces a potential regulatory phenotype in Th17 cells, highlighting the therapeutic potential of targeting pathogenic Th17 cells in autoimmunity. In this review, we discuss the current knowledge of Th17 cell plasticity and heterogeneity in autoimmune kidney diseases with a special focus on the underlying mechanisms of this process and debate if Th17 cell plasticity is beneficial or harmful to renal inflammation.