Targeted T_Regs tame autoimmune disease

Credit: MACMILLAN/Paul Bricknell

The 'holy grail' of immunology is to find the right tools to precisely direct immune responses into desired directions — arming the immune system to destroy cancer cells, or calming it to stop tissue destruction in autoimmune diseases. Regulatory T cells (T_Regs) have attracted considerable attention, as these cells can tame their inflammatory counterparts. Reporting in PNAS, Wright and co-workers present a strategy to convert primary T cells into T_Regs for adoptive transfer to achieve targeted immune suppression in a mouse model of arthritis.

The clinical translation of targeted therapy with T_Regs has been hampered by the fact that T_Regs require T cell receptor (TCR) ligation by a specific antigen to fully activate their suppressive function. Isolating and expanding antigen-specific T_Regs from the natural polyclonal T cell repertoire is difficult, and in autoimmune disorders the initiating antigen that is responsible for pathology is often unknown. In this study, the authors tested two strategies to engineer efficient T_Regs that can be 'switched on' by stimulating a retrovirally introduced TCR. The first strategy involved the insertion of an ovalbumin (OVA)-specific TCR gene construct into naturally occurring T_Regs, whereas the second approach involved transducing total CD4⁺ T cells with the OVA–TCR construct and the gene encoding forkhead box protein P3 (FOXP3), a transcription factor that converts conventional CD4⁺ T cells into T_Regs.

In vitro experiments showed that both strategies lead to the development of functional T_Regs that are capable of immune suppression, which is strongly enhanced in the presence of the OVA antigen. To test whether these cells retain their suppressive function in vivo, the authors used a mouse model of antigen-induced arthritis. Disease was induced by immunizing mice with methylated bovine serum albumin (mBSA) followed by intra-articular knee rechallenge with mBSA, resulting in T cell-mediated tissue damage. The engineered T_Regs were injected before mBSA rechallenge, and each animal received an injection of mBSA and OVA in one knee, and mBSA alone in the other (the control knee). The engineered T_Regs were shown to home to the OVA-injected knee and substantially decrease inflammatory knee swelling and arthritic bone destruction, while having no effect on the control knee.

Importantly, suppression occurred even though the regulatory and the pathogenic T cells recognized distinct antigens. This suggests that T_Regs could be engineered to express TCRs that recognize tissue-specific antigens in the target organ of autoimmune disease, thus leading to selective homing and local suppression of pathogenic T cells, irrespective of their antigen specificity. If such experiments can be translated to the human setting, it could pave the way for highly targeted T_Reg therapies that provide effective control of autoimmune-mediated tissue damage, without impairment of systemic immunity or the need for systemic immune suppression.