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Antigen-specific regulatory T cells: are police CARs the answer?

      Cellular therapy with T-regulatory cells (Tregs) is a promising strategy to control immune responses and restore immune tolerance in a variety of immune-mediated diseases, such as transplant rejection and autoimmunity. Multiple clinical trials are currently testing this approach, typically by infusing a single dose of polyclonal Tregs that have been expanded in vitro. However, evidence from animal models of Treg therapy has clearly shown that antigen-specific Tregs are vastly superior to polyclonal cells, meaning that fewer cells are needed for the desired therapeutic effect. Traditional methods to obtain antigen-specific Tregs include antigen-stimulated expansion or T-cell receptor (TCR) overexpression. However, these methods are limited by low cell numbers, complex manufacturing procedures, and knowledge of patient-specific TCRs which recognize disease-relevant MHC-peptide complexes. Recently, several groups have explored the potential to use chimeric antigen receptors (CARs) to generate antigen-specific Tregs. Here, we discuss the progress in this field and highlight the major outstanding questions that remain to be addressed as this approach moves toward clinical applications.

      Abbreviations:

      CEA (carcinoembryonic antigen), CAR (chimeric antigen receptor), EAE (experimental autoimmune encephalomyelitis), HLA (human leukocyte antigen), HSCT (Hematopoietic stem cell transplantation), LAP (latency-associated peptide), PBMC (peripheral blood mononuclear cell), Treg (T-regulatory cells), TCR (T-cell receptor), TGF (Transforming growth factor), TNP (2,4,6-trinitrophenol), TNBS (2,4,6-trinitrobenzene sulfonic acid), WT (wild-type)
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