Abstract
FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30–35% of CD4+ T cells) during the late stage (days 21–90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.
Highlights
Regulatory T cells (Tregs) play crucial roles in peripheral tolerance and tissue homeostasis in the immune system.[1,2,3] They express FoxP3 as a major master transcription factor and suppress excessive immune responses by recognizing various self and foreign antigens
The levels of pathogenic IL-17A+ Th17 cells peaked 10 days after crescentic GN (cGN) induction, while the IFNγ+ Th1 and Treg proportion reached a plateau on day 21 and remained at high levels for at least 3 months (Fig. 1b), which was consistent with a previous report.[18]
ST2 and Areg are essential for kidney Treg accumulation and function Since ST2 and Areg are highly expressed in GATA3+ Tregs, we investigated the role of IL-33/ST2 and Areg in kidney Treg development and function
Summary
Regulatory T cells (Tregs) play crucial roles in peripheral tolerance and tissue homeostasis in the immune system.[1,2,3] They express FoxP3 as a major master transcription factor and suppress excessive immune responses by recognizing various self and foreign antigens. The localized microenvironment seems to play pivotal roles in acquiring phenotypes of tissue Tregs.[13]
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