Engineering Specificity and Function of Therapeutic Regulatory T Cells.

Jenny L Mcgovern,Graham P Wright,Hans J Stauss

doi:10.3389/fimmu.2017.01517

Abstract

Adoptive therapy with polyclonal regulatory T cells (Tregs) has shown efficacy in suppressing detrimental immune responses in experimental models of autoimmunity and transplantation. The lack of specificity is a potential limitation of Treg therapy, as studies in mice have demonstrated that specificity can enhance the therapeutic potency of Treg. We will discuss that vectors encoding T cell receptors or chimeric antigen receptors provide an efficient gene-transfer platform to reliably produce Tregs of defined antigen specificity, thus overcoming the considerable difficulties of isolating low-frequency, antigen-specific cells that may be present in the natural Treg repertoire. The recent observations that Tregs can polarize into distinct lineages similar to the Th1, Th2, and Th17 subsets described for conventional T helper cells raise the possibility that Th1-, Th2-, and Th17-driven pathology may require matching Treg subsets for optimal therapeutic efficacy. In the future, genetic engineering may serve not only to enforce FoxP3 expression and a stable Treg phenotype but it may also enable the expression of particular transcription factors that drive differentiation into defined Treg subsets. Together, established and recently developed gene transfer and editing tools provide exciting opportunities to produce tailor-made antigen-specific Treg products with defined functional activities.

Highlights

Engineering Specificity and Function of Therapeutic Regulatory T CellsReviewed by: David William Scott, Uniformed Services University of the Health Sciences, United States Raymond John Steptoe, The University of Queensland, Australia
Inherent checkpoints ensure that an immune response normally only occurs in response to genuine threats from pathogens
We, and others, have explored redirecting the specificity of bulk Treg populations by the gene transfer of a disease-relevant T cell receptor (TCR) [9]. This process involves the genetic engineering of Treg with genes encoding TCR or chimeric antigen receptors (CARs) to target Treg specificity to antigens that are present at the sites of autoimmunity and absent in healthy tissues

Summary

Engineering Specificity and Function of Therapeutic Regulatory T Cells

Reviewed by: David William Scott, Uniformed Services University of the Health Sciences, United States Raymond John Steptoe, The University of Queensland, Australia. Specificity and Function of Therapeutic Regulatory T Cells. Adoptive therapy with polyclonal regulatory T cells (Tregs) has shown efficacy in suppressing detrimental immune responses in experimental models of autoimmunity and transplantation. We will discuss that vectors encoding T cell receptors or chimeric antigen receptors provide an efficient gene-transfer platform to reliably produce Tregs of defined antigen specificity, overcoming the considerable difficulties of isolating low-frequency, antigen-specific cells that may be present in the natural Treg repertoire. The recent observations that Tregs can polarize into distinct lineages similar to the Th1, Th2, and Th17 subsets described for conventional T helper cells raise the possibility that Th1-, Th2-, and Th17-driven pathology may require matching Treg subsets for optimal therapeutic efficacy. Together, established and recently developed gene transfer and editing tools provide exciting opportunities to produce tailor-made antigen-specific Treg products with defined functional activities

INTRODUCTION

REDIRECTING THE SPECIFICITY OF Tregs USING GENE THERAPY

STRATEGIES TO IDENTIFY THE MOST APPROPRIATE CELL FOR GENE ENGINEERING

CONVERTING CONVENTIONAL T CELLS INTO Tregs THROUGH GENE ENGINEERING

CONCLUSION