The suppressive function of human CD8(+) iTregs is inhibited by IL-1β and TNFα.

CD8(+) Tregs display an immunoregulatory activity and may play an essential role in the immunopathology of several diseases. Therefore, their therapeutic potential is exquisite and further studies on their differentiation and function are essential. The aim of this study was to evaluate the role of the innate immune system in CD8(+) iTreg differentiation and function. Naive human CD8(+) CD25(-) CD45RA(+) T cells were cultured in Treg-inducing conditions with or without IL-1β, TNFα or monocyte-derived dendritic cells (DCs). The differentiation of CD8(+) CD127(-) CD25(hi) FoxP3(hi) -induced Tregs (CD8(+) iTregs) is dependent on TGF-β1 and IL-2, which had synergistic effect upon their differentiation. CD8(+) iTregs were also induced in a coculture with allogeneic mature DCs (mDCs). The CD8(+) iTregs suppressive function was confirmed, which was diminished in the presence of IL-1β and TNFα. The IL-1β-prevented suppressive function was associated with reduced secretion of IL-10 and IFNγ, whereas the presence of TNFα did not affect their secretion. Furthermore, the presence of TNFα reduced IL-10 and TGF-β1 secretion by CD8(+) iTregs, whereas only IL-10 secretion was decreased by IL-1β. Together, these results suggest that IL-1β and TNFα prevent IL-2- and TGF-β1-driven CD8(+) iTregs suppressive function in human T cells. Such pro-inflammatory innate immune response possibly mediates its negative tolerogenic effect through reduced IFNγ-, IL-10- and TGF-β1-driven mechanism.