Abstract
Cell therapy with polyclonal regulatory T cells (Tregs) has been translated into the clinic and is currently being tested in transplant recipients and patients suffering from autoimmune diseases. Moreover, building on animal models, it has been widely reported that antigen-specific Tregs are functionally superior to polyclonal Tregs. Among various options to confer target specificity to Tregs, genetic engineering is a particularly timely one as has been demonstrated in the treatment of hematological malignancies where it is in routine clinical use. Genetic engineering can be exploited to express chimeric antigen receptors (CAR) in Tregs, and this has been successfully demonstrated to be robust in preclinical studies across various animal disease models. However, there are several caveats and a number of strategies should be considered to further improve on targeting, efficacy and to understand the in vivo distribution and fate of CAR-Tregs. Here, we review the differing approaches to confer antigen specificity to Tregs with emphasis on CAR-Tregs. This includes an overview and discussion of the various approaches to improve CAR-Treg specificity and therapeutic efficacy as well as addressing potential safety concerns. We also discuss different imaging approaches to understand the in vivo biodistribution of administered Tregs. Preclinical research as well as suitability of methodologies for clinical translation are discussed.
Highlights
Regulatory T cells (Tregs) are a subset of T cells that function to maintain homeostasis and prevent autoimmunity [1]
Tregs make up 5–10% of the CD4+ T cell population [2] and are characterized by co-expression of CD4, CD25, the transcription factor Forkhead box protein 3 (FOXP3) and low levels of CD127
We have shown that A2-chimeric antigen receptors (CAR)-Tregs were functionally superior compared to polyclonal Tregs in vitro and in vivo in a humanized mouse model of BRG mice bearing a human skin transplant reconstituted with 5:1 PBMCs to CAR-Tregs, assessed by histological analysis 5 weeks post adoptive transfer [51]
Summary
Regulatory T cells (Tregs) are a subset of T cells that function to maintain homeostasis and prevent autoimmunity [1]. Tregs make up 5–10% of the CD4+ T cell population [2] and are characterized by co-expression of CD4, CD25, the transcription factor Forkhead box protein 3 (FOXP3) and low levels of CD127. Conventional human T cells (Tconv) can transiently express FOXP3, high FOXP3 levels and demethylation of the Treg specific demethylated region (TSDR), a conserved region within the FOXP3 gene, are distinct features of Tregs [3].
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