The immune response is a prerequisite for the development of CD4⁺Foxp3⁺ regulatory T cells in transplantation

CD4⁺Foxp3⁺ regulatory T cells (Tregs) are critical in maintaining the peripheral tolerance and homeostasis of the immune system, yet their development and role in transplantation are poorly understood. Here we show that the levels of Tregs in neonatal transplant tolerant mice are similar to the levels in naive mice when they are kept in a state of homeostasis devoid of an immune response. An increased frequency of Tregs was observed only in recipients with allograft rejection, in naive mice that received alloantigens, or in tolerant mice adoptively transferred with alloreactive T cells. Even though an antigen-specific immune response is a prerequisite for the development of Tregs, both antigen-specific and nonspecific Tregs are generated in this process. We conclude that Tregs are induced and function in an inflammatory environment and in a negative feedback loop.