Genetically engineered T regulatory cells: a future therapy for multiple sclerosis? – TCRinMS

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) characterized by multifocal demyelination, glial scar formation, disabling axonal damage, and accumulation of immune cells at lesion sites. The immune system contributes to MS pathogenesis because immune-related genes influence disease susceptibility, and immune-modulating drugs can limit MS progression. This deleterious involvement of the immune system in MS is associated with defects in the suppressive function of regulatory CD4+ T cells expressing the transcription factor Foxp3 (Tregs), which are required for the maintenance of normal immune homeostasis. These cells are protective in autoimmune diseases of the CNS. In experimental autoimmune encephalomyelitis (EAE), a preclinical model for MS, they can inhibit both the initiation and the progression of the disease. A therapeutic approach for MS might therefore be to increase the number of functionally suppressive Tregs in affected patients, for instance through autologous adoptive Treg cell therapy since Tregs from autoimmune patients can recover effective suppressive functions upon ex vivo expansion. In experimental studies monoclonal Tregs expressing a TCR recognizing a disease relevant autoantigen were markedly superior to polyclonal Tregs in cellular therapies. For instance, myelin-reactive TCR transgenic Tregs cured recipient mice from EAE, while polyclonal Tregs had no effect. Thus, the most attractive Tregs for a cell-based therapy against autoimmune disease would be those patient’s own Tregs that express TCR reacting against disease-relevant autoantigens. However, such cells are rare and difficult to isolate. A major limitation to overcome is therefore to obtain sufficient numbers of relevant autoantigen-specific Tregs. In collaboration with experts in TCR engineering, S. Fillatreau established a protocol to solve this difficulty by the genetic engineering of polyclonal Tregs through TCR gene transfer. Such engineered Tregs fully protected recipient mice from a CD4+ T cell-mediated EAE in adoptive transfer experiments. We therefore propose that polyclonal Tregs engineered through TCR gene transfer are a particularly attractive cellular platform for the development of a tolerogenic cell-based therapy for MS and other autoimmune diseases. It is now essential to evaluate the range of the protective action of such cells against pathogenic mechanisms relevant in human autoimmune diseases. Accordingly, we propose in this project to examine, using different EAE models, whether TCR-engineered Tregs can suppress CNS autoimmune disease driven by other pathogenic mechanisms than CD4+ T cells, including B cells, antibodies, and CD8+ T cells, which are all important in human MS. In addition, we will test the capacity of “monoclonal” TCR-engineered Tregs to control pathogenic T cells reacting against other CNS antigens than the one they recognize, which is important given the still poorly understood complexity of the autoimmune response implicated in MS, and is plausible considering that Tregs activated via their TCR can exert bystander suppressive functions locally. Finally, we will test several approaches to increase the protective function of these cells, based first on our demonstration of the role of the functional avidity of the grafted TCR for the target autoantigen in the protective effect of these cells, and second on the central role of interleukin (IL)-2 in the regulatory activity and homeostasis of Tregs. By pursuing our highly innovative line of research, this project will provide a unique contribution for the development of engineered Tregs as a cell based therapy for autoimmune disease, which is likely to become a realistic possibility considering the considerable efforts currently undertaken to characterize Tregs in patients, and to use them for treatment.