Abstract
Regulatory T cells (Tregs) have been shown to play a protective role in glomerulonephritis (GN) and Foxp3 is a master transcription factor in Treg development. In this study, we examined the functional role and mechanisms of Foxp3 in a mouse model of accelerated anti-glomerular basement membrane (anti-GBM) GN induced in antigen-primed Foxp3 transgenic (Tg) mice. Compared with littermate of wildtype (WT) mice in which induced severe crescentic GN developed with progressive renal dysfunction, Foxp3 Tg mice had reduced crescent formation, urinary protein excretion, plasma creatinine and decline in creatinine clearance. The protective role of Foxp3 in crescentic GN was associated with a markedly suppressed expression of proinflammatory interleukin-1 beta (IL-1β), tumour necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1), and diminished infiltration of the kidneys by CD3+ T cells and F4/80+ macrophages. Moreover, overexpression of Foxp3 resulted in a significant increase in CD4+ Foxp3+ Tregs systemically and in the diseased kidneys, thereby blunting Th1, Th2, and Th17 responses systemically and in the kidneys. In conclusion, Foxp3 protects against kidney injury in crescentic GN through enhancement of Treg numbers and function, and suppression of Th1, Th2 and Th17 immune responses at the systemic and local tissue levels.
Highlights
Tregs play a crucial role in immune homeostasis and tolerance[6]
Real-time PCR demonstrated that WT mice with anti-GBM GN had a marked increase in mRNA levels of IL-1β, TNF-α, and MCP-1 in the diseased kidney (Fig. 2A–C), which was infiltrated by large numbers of CD3+ T cells and F4/80+ macrophages (Fig. 2D–E)
Foxp[3] Tg mice had attenuated (1) glomerular necrosis and crescent formation, (2) proteinuria, (3) plasma creatinine increase, (4) creatinine clearance decline, and (5) renal inflammation mediated by T cells and macrophages and the proinflammatory cytokines (TNF-α, IL-1β and MCP-1)
Summary
Tregs play a crucial role in immune homeostasis and tolerance[6]. Decreased number of, and impaired immunosuppression by, Tregs are associated with many types of kidney diseases, including immune-mediated kidney disease, proteinuric renal disease and acute kidney injury[7]. Its pivotal role is demonstrated in the paediatric X-linked multiple organ autoimmune disorder named immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), in which mutation in FOXP3 results in loss of Tregs, severe inflammation, lymphoproliferation, and hyperactive T cell infiltration in multiple organs[12]. This disease phenotype is recapitulated in the X-linked scurfy mouse mutant[13], and can be rescued by adoptive transfer of Tregs. In models of kidney disease, adoptive transfer of Foxp3-transduced polyclonal T cells protects against chronic renal injury induced by doxorubicin (Adriamycin) in vivo[14]. We reveal the mechanisms by which Foxp[3] suppresses anti-GBM crescentic GN in the Foxp[3] transgenic (Tg) mouse
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