Regulatory T cells in solid organ transplantation

Abstract

The induction of graft tolerance remains the holy grail of transplantation. This is important as chronic allograft dysfunction and the side effects of immunosuppression regimens place a major burden on the lives of transplant patients and their healthcare systems. This has mandated the need to understand the immunobiology of graft rejection and identify novel therapeutics. Regulatory T (Treg) cells play an important role in modulating pro-inflammatory microenvironments and maintaining tissue homeostasis. However, there are fundamental unanswered questions regarding Treg cell immunobiology. These cells are a heterogeneous entity with functionally diverse roles. Moreover, the adoption of novel deeper immunophenotyping and genomic sequencing technologies has identified this phenotype and function to be more complex than expected. Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. From a clinical perspective, the recent decade has seen different clinical teams commence and complete first-in-man clinical trials utilising Treg cells as an adoptive cellular therapy. In this review, we discuss these trials from a translational perspective with an important focus on safety. Finally, we identify crucial knowledge gaps for future study.

Keywords: FOXP3; Treg; clinical trial; regulatory T cells; safety; transplant.

Figure 1

How CD4⁺ T cells can be split based on FOXP3 and CD45RA expression levels to identify Treg cell subpopulations. The naïve Treg cells are FOXP3⁺ and CD45RA⁺. However, the activated Treg cells are relatively much more positive for FOXP3⁺ but CD45RA⁻ instead. Finally, there is an effector T‐cell subpopulation which is also FOXP3⁺ and CD45RA⁻. This final subpopulation does not have immunosuppressive functions and releases pro‐inflammatory cytokines.

Figure 2

Diversity of Treg cells and their subpopulations. (a) shows Treg cells split into distinct populations depending on their expression profile of chemokine receptors. (b) shows a range of intracellular and/or extracellular markers identified on Treg cells. These markers are not exhaustively demonstrated in the diagram but are to give an indicator of the complexity of whichever phenotypic classification one utilises.

Figure 3

Schematic demonstration of a Treg cell and the contributors to the Treg program. Treg cells can be modulated by numerous mechanisms; T‐cell receptor (TCR) stimulation from antigen‐presenting cells (APCs) or effector T cells; cytotoxic T‐lymphocyte antigen 4 (CTLA4); programmed death 1 (PD1); and interleukin‐2 (IL‐2) via CD25. There is a complex interaction between FOXP3 and other transcription factors [e.g. nuclear factor of activated T cells (NFAT), activator protein‐1 (AP‐1)], and these interact with the FOXP3 gene across the different loci. Although several intracellular mechanisms are triggered, they all centre on the crucial cross‐talk between the FOXP3 gene and others to transcribe an optimal ‘Treg program’. This ‘Treg program’ is then put into action via protein translation and ultimately facilitates Treg function via the numerous mechanisms illustrated.