Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. The innate immune system plays a significant role in the pathogenesis of autoimmune diseases. However, its role in the differentiation and function of human CD4+ induced TRegs (iTRegs) is currently unclear. In this study we investigated the effect of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and IL-1β upon the differentiation and function of human CD4+FoxP3+ iTRegs.
Naïve human CD4+CD25- T cells, isolated from both cord blood (CB) and adult peripheral blood (PB) were cultured under various stimulatory conditions with/without TNFα and IL-1β. The CD4+FoxP3+ iTRegs were characterized as CD4+CD127-CD25highFoxP3high iTRegs and their suppressive function evaluated.
TNFα and IL-1β significantly affected the differentiation of human CD4+FoxP3+ iTRegs in a dose and time dependent manner. Low dose and short term conditions promoted their differentiation while high dose and long term conditions were inhibitory. In addition, the suppressive function of the CD4+FoxP3+ iTRegs was inhibited by TNFα and IL-1β. This inhibitory effect of TNFα and IL-1β was associated with a significant reduction of the transforming growth factor β receptor type II (TβRII) expression and IL-2 secretion. However, their IL-10 secretion was not affected and no IL-35 secretion was observed in any of the culture conditions tested.
We conclude that the in vitro induction of human CD4+FoxP3+ iTRegs is mediated through TβRII and IL-2 dependent mechanism. The regulatory effect of TNFα and IL-1β on CD4+FoxP3+ iTReg differentiation is dynamic and may to some extent reflect the magnitude and persistence of the initial pro-inflammatory response.
Author(s): Snaefridur Halldorsdottir, Una Bjarnadottir, Laufey Geirsdottir, Brynja Gunnlaugsdottir, and Bjorn Runar Ludviksson