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Regulatory T cells (Tregs) are crucial immune cells that initiate a tolerable immune response. Transforming growth factor-beta (TGFβ) is a key cytokine produced by Tregs and plays a significant role in stimulating tissue fibrosis. Systemic sclerosis, an autoimmune disease characterized by organ fibrosis, is associated with an overrepresentation of regulatory T cells. This review aims to identify Treg-dominant tolerable host immune reactions and discuss their association with scleroderma and end-stage organ failure. End-stage organ failures, including heart failure, liver cirrhosis, uremia, and pulmonary fibrosis, are frequently linked to tissue fibrosis. This suggests that TGFβ-producing Tregs are involved in the pathogenesis of these conditions. However, the exact significance of TGFβ and the mechanisms through which it induces tolerable immune reactions during end-stage organ failure remain unclear. A deeper understanding of these mechanisms could lead to improved preventive and therapeutic strategies for these severe diseases.