Heterogeneity of regulatory T cells: which type is best for the treatment of inflammatory and autoimmune diseases?

In this blog, we will discuss a study by Sanquin that identified the most optimal T cells for immunotherapy, by using SORT-seq.

Adoptive cell therapy (ACT) is a type of immunotherapy in which T cell are isolated from the body, expanded, and placed back. These isolated T cells can be engineered in order to specifically target for example tumor cells.

A small proportion of T cells are regulatory T cells (Tregs), which can develop directly in the thymus or from other T cell subsets in the periphery. Tregs can suppress immune responses to prevent over-reactivity of the immune system against cells of its own body, a process called immunological tolerance.

Interestingly, Tregs can also be used for ACT. Instead of targeting cancer cells, the expanded population of Tregs can suppress immune responses in the body. This can be used to enhance tolerance in autoimmune diseases or prevent transplant rejection after organ transplantation.

An important issue with Treg ACT is the isolation of stable Tregs with adequate functional potency. Tregs in the thymus are more stable compared to Tregs in the periphery. Therefore, Tregs in the thymus, which are usually developing Tregs, are most suitable for ACT. Increased understanding of the heterogeneity in the Treg population and development of Tregs in the thymus contributes to more efficient ACT.

In this study, single-cell RNA sequencing was used to delineate three major Treg developmental stages in the human thymus. This research was published in the Journal of Immunology in January 2022.

New findings from this study

In this study, researchers defined three major developmental stages of Tregs in the human thymus. The first stage is called the pre-Treg I stage, followed by the second stage called early pre-Treg II. The last stage is the late pre-Treg II stage. Each developmental stage is characterized by the expression of a specific gene set. Next to these developing Tregs, this study also found recirculating mature Tregs in the thymus that originate from the periphery.

As mentioned in the introduction, developing Tregs in the thymus are most suitable for ACT. Therefore, a selection of Tregs based on their markers could contribute to efficient ACT. In addition, exclusion of recirculating mature Tregs present in the thymus could contribute to a more efficient ACT.

Contribution of single-cell RNA sequencing

In this study, the single-cell RNA sequencing platform SORT-seq was performed at Single Cell Discoveries to analyze Tregs isolated from a human thymus. Single-cell RNA sequencing resulted in a transcriptome database from 344 Tregs. This was further analyzed at Sanquin.

Cells were clustered based on the transcriptome dataset, yielding three populations of Tregs. This data, combined with flow cytometry data, resulted in the delineation of three developmental stages of Tregs in the human thymus, based on the expression of various markers.

Future research is needed to understand how these new insights in the development of Tregs in the human thymus contribute to ACT and the treatment of inflammatory and (auto)immune diseases.

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