Abstract
The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction. We generated human Tregs expressing a high-affinity GAD555–567-reactive TCR (clone R164), as well as the lower affinity clone 4.13 specific for the same peptide. We demonstrated that de novo Treg avatars potently suppress antigen-specific and bystander responder T-cell (Tresp) proliferation in vitro in a process that requires Treg activation (P < 0.001 versus unactivated Tregs). When Tresp were also glutamic acid decarboxylase (GAD)-reactive, the high-affinity R164 Tregs exhibited increased suppression (P < 0.01) with lower Tresp-division index (P < 0.01) than the lower affinity 4.13 Tregs. These data demonstrate the feasibility of rapid expansion of antigen-specific Tregs for applications in attenuating β-cell autoimmunity and emphasize further opportunities for engineering cellular specificities, affinities, and phenotypes to tailor Treg activity in adoptive cell therapies for the treatment of type 1 diabetes.
Highlights
T-cell receptor (TCR) transgenic regulatory T cells (Tregs) may represent a promising personalized treatment for T-cell-mediated autoimmune diseases such as type 1 diabetes
We recently identified T cells expressing the TCR β-chain complementarity determining region (CDR3β) of the glutamic acid decarboxylase (GAD) 4.13 clone from tissues of seven organ donors with type 1 diabetes, including the pancreatic islets of one type 1 diabetes subject
Over 94% of Jurkat cells transduced with either the R164 or 4.13 TCR lentiviral construct were double positive for both TCRVα12.1 and Vβ5.1 with comparable mean fluorescence intensity (MFI) (Figure 1B)
Summary
T-cell receptor (TCR) transgenic regulatory T cells (Tregs) may represent a promising personalized treatment for T-cell-mediated autoimmune diseases such as type 1 diabetes. A curative therapy that targets the underlying immunological cause of disease to restore antigen-specific immunological tolerance represents an essential objective for the preservation of β-cell mass and function in the treatment of type 1 diabetes [1]. Non-specific polyclonal immunotherapies, including immunoregulatory or depleting agents [e.g., alefacept (human LFA-3/IgG1-Fc fusion protein), teplizumab or otelixizumab (anti-CD3), and rituximab (anti-CD20)], have been better tolerated and offered some temporary efficacy but not long-term induction of tolerance [4,5,6,7,8,9,10]. A safe treatment that controls persistent immune memory and induces long-term tolerance is needed
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