Genetic engineering of antigen-specific regulatory T cells

Regulatory T cells (Tregs) potently suppress a variety of innate and adoptive immune responses mediated by T effector cells (Teff). However, because of their low number (comprising only minor subset (4-10%) of the total CD4 T cell population) and their multiple specificities, large numbers of expanded antigen-specific Tregs are required in order to suppress an ongoing inflammatory response. This scarcity of Tregs greatly limits their clinical use against autoimmune inflammatory conditions. To overcome the scarcity of antigen-specific Tregs, several attempts have been made to redirect the specificity of Tregs to a pre-defined target antigen. In this chapter, we review three approaches to endow Tregs with the required novel specificity; all rely on the ability to genetically engineer the recognition of Treg by their transduction with any receptor-gene of interest. The first approach utilizes a chimeric receptor whose specificity is comprised of a class-II-peptide complex; this receptor redirects the genetically modified Tregs against pathogenic antigen-specific effector T cells, resulting in suppression of an experimental model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). The second approach makes use of TCR α and β chain gene transduction to generate MHC-1:peptide specific Tregs that were shown to suppress arthritis and rejection of a non-HLA-matched transplant. The third approach is based on an antibody-based chimeric receptor, which we have used to generate murine Tregs that suppress TNBS colitis in a murine model. In this review, we describe the activity of each of these modified Tregs, compare their reactivity to unmodified nTreg, and discuss their potential as well as obstacles towards future clinical application.