Reprogramming T Cell Specificity to Suppress Autoreactive T Cells in Type 1 Diabetes

Abstract

Abstract Effector T cells (Teff) in Type 1 Diabetes (T1D) recognize antigenic targets on pancreatic β cells, thereby killing them. Insulin-derived epitopes are targeted first, followed by rapid epitope spreading, leading to progressive destruction of pancreatic islets, causing insulitis and T1D. Curbing these autoimmune responses is key to the development of immunotherapies to treat T1D. In this study, we tested the proof-of-concept of two strategies to treat T1D by reprogramming T cell specificity. We have developed cell-surface receptors called SABRs (Signaling and Antigen-presenting Bifunctional Receptors), which present a peptide-MHC complex on the extracellular domain and link it with a CD28-CD3ζ signaling domain. The intracellular signaling domains in SABRs are capable of activating T cell function. The extracellular domains can recognize TCRs specifically. We successfully demonstrated that SABRs presenting peptide epitopes on human and mouse, class I and class II MHC complexes are able to induce a functional signal through the NFAT pathway. We tested two complementary approaches to use SABRs to engineer T cells. In the first approach, we transduced human Treg cells with SABRs. SABR-armed Treg cells were able to secrete IL-10 in response to T cells bearing a diabetogenic TCR. In the second approach, we transduced human CD8+ T cells with SABRs. SABR-modified CD8+ T cells were able to specifically lyse target cells bearing a diabetogenic TCR. Ongoing studies will determine if Treg-mediated suppression or CD8+ T cell-mediated elimination of diabetogenic Teff cells will be an efficient strategy for immunotherapy for T1D. If successful, these approaches will also be applicable to other autoimmune diseases such as Multiple Sclerosis.