The NF-kappaB Signalling Pathway is Involved in the LPS/IL-2-induced Upregulation of FoxP3 Expression in Human CD4+CD25high Regulatory T Cells

Regulatory T cells (Treg) have been found to be central for host defense regulation against microbial antigens, the prevention of allergic and autoimmune diseases and the suppression of effective tumor immune responses. However, the influence of the microenvironment and the mechanisms leading to their activation in the periphery still remain unclear. In vitro infection models revealed that survival and suppressive function of Treg is improved when they are confronted with lipopolysaccharide (LPS). Because LPS initiates signalling via the receptor Toll-like receptor 4 (TLR4) and the consequent activation of the transcription factor nuclear factor-kappaB (NF-kappaB), we investigated TLR4 expression and NF-kappaB regulation in human Treg. We demonstrated that LPS in combination with IL-2 induces human CD25(+)FoxP3(+) T cells in vitro. FoxP3 expression of purified natural Treg increased and suppressive capacity was markedly improved compared with unstimulated Treg upon stimulation with LPS/IL-2. Furthermore, blockade of the NF-kappaB pathway by a selective inhibitor of IkappaB kinase (IKK)beta abrogated the upregulation of FoxP3 expression. Taken together, our results suggest an important role of the NF-kappaB signalling pathway for the induction and modulation of suppressive function of natural Treg, if they are confronted with TLR4-stimulating agents such as Gram-negative bacteria.