Potential of targeting TGF-β for organ transplant patients

Abstract

TGF-β was originally considered as an immunoregulatory cytokine, but accumulating data demonstrate that it also plays a critical role in development of effector immunity. Since TGF- β has a potent ability to alter immune responses, modulation of the TGF-β pathway for treatment of transplantation patients could be effective if carried out in a target selective manner. This review will focus on the role of TGF-β in T cell differentiation and discuss the prospect of TGF-β as the therapeutic target of lung transplantation acceptance.

Figure 1. Effect of TGF-β on p53-induced CD28-dependent T cell apoptosis

When naive CD4 T cells are stimulated by plate-bound anti-CD3/anti-CD28 antibodies to induce apoptosis, the presence of TGF-β inhibits apoptosis. If IL-4 is present, naive CD4 T cells differentiate into Th9 cells, while presence of IL-6 promotes development of Th17 cells.

Figure 2. Transcriptional control of naive T cell differentiation by TGF-β and other cytokines

In naive CD4 T cells activated by antigens, TGF-β and IL-2 promote the expression of Foxp3, an essential transcription factor for iTregs development. When IL-6 is present along with TGF-β, pro-inflammatory IL-17 production is induced via activation of RORγt and STAT3. The combination of TGF-β with IL-4 leads to the expression of IL-9 by SMAD complex and STAT6.

Figure 3. Summary of TGF-β effect on CD4 T cells

TGF-β has both immunoregulatory and immunogenic effect on CD4 T cells. In the regulatory wing, TGF-β can directly suppress Th0 activation and block cytokine production while promoting the development of inducible Tregs. In the effector wing, TGF-β can promote the differentiation of Th9 and Th17 cells. For transplantation, it is essential to develop the method to enhance the immunoregulatory functions of TGF-β while blocking immunogenic effect. Treg: Regulatory T cell.