TGFβ induced FoxP3+ regulatory cells prevent Th1 mediated colitis in vivo

Loss of immune tolerance is a key feature at the basis of many autoimmune human diseases such as IBDs. Tolerance is achieved through both central deletion of self reactive T cells and the peripheral control of potentially autoaggressive effector cells by means of specialized regulatory cells. A subgroup of these regulatory cells, characterized by the constitutive expression of CD25, GITR and CTLA–4, have been recently found to express the transcription factor FoxP3, being responsible for the regulatory phenotype of these cells.

Although these cells have been demonstrated to originate from the thymus during the first weeks after birth both in human and mice, there are evidences sustaining that these cells could also be generated in periphery.

TGFβ, a key molecule involved in the control of the immune system, represents a good candidate for the peripheral generation of regulatory T cells, as suggested by both the general autoimmune process observed in mice knocked out for this cytokine.

In the present work we have demonstrated that TGFβ is able to induce FoxP3 in murine naïve CD4+CD25-FoxP3- and to determine in these cells the acquisition of regulatory properties in vitro. Moreover, the TGFβ induced FoxP3 expression determines a downregulation of Smad7, a negative regulator of the TGFβ pathway, consequently enhancing Smad3/4 activity. Thus, TGFβ signalling in these cells induces a positive autoregulatory loop due to FoxP3 induced downregulation of Smad7.

The regulatory properties of these cells were further demonstrated in vivo, where in vitro generated CD4+FoxP3+ regulatory cells where able to prevent the Th1 mediated colitis induced by the transfer of CD4+CD62L+ cells in Rag1 knockout mice (Rag1-/-).

Findings reported in this work provide a mechanism though which TGFβ plays a pivotal role in inducing and maintaining peripheral tolerance by means of the generation of FoxP3+ regulatory T cells from the CD4+ naïve cell pool. Moreover the effect exerted by TGFβ induced FoxP3 on Smad7, outline the intriguing scenario in which the abnormal upregualtion of Smad7 observed in Crohn's disease could alter the physiological development of regulatory cells into the lamina propria of the affected patients.

Key words

FoxP3 - TGFβ - Th1