Differentiation pathways in human Treg cells revealed

Akash Singh, Banaras Hindu University

Immune tolerance relies on FOXP3+ regulatory T (T_reg) cells in humans. Their heterogeneity and distinction, on the other hand, have always been a point of contention. A Chinese research team has used single-cell RNA (scRNA) and T cell receptor sequencing to isolate T_reg cells from healthy people and stem cell transplant patients with or without acute graft-versus-host disease (aGVHD) and they were able to reveal the differentiation pathways in human Treg cells using single-cell RNA sequencing (scRNA-seq).

Regulatory T cells (T_reg):

Treg cells are a population of CD4+ T cells that is highly immunosuppressive and expresses the transcription factor forkhead box protein P3 (FOXP3). They’re thought to be heterogeneous, controlling immune responses and maintaining peripheral tolerance.

Treg cells are divided into two types based on their origins: Thymus derived T_reg (tT_reg) cells, which develop in the thymus and make up the majority of Treg cells in secondary lymphoid organs, and Peripheral T_reg (pT_reg) cells, which arise from conventional T (t_con) cells at peripheral sites with additional FOXP3 expression. Resting or naive Treg cells (CD45RA+FOXP3lo/CD25lo), Effector T_reg cells (CD45RA-FOXP3hi/CD25hi), and pseudo-T_reg cells (CD45RA-FOXP3lo/CD25lo) are the three subpopulations of CD4+FOXP3+T_reg cells seen in human peripheral blood (PB).

Single-cell RNA sequencing (scRNA seq):

There is a huge variety of cell types, states, and interactions in human tissues. Single-cell RNA-seq (scRNA-seq) provides a glimpse into what genes are being expressed at the level of individual cells, which helps researchers better comprehend these tissues and cell types.

Prior to scRNA-seq, transcriptome analysis was done with bulk RNA-seq, which is a simple method for comparing cellular expression averages. This method may be the best choice if you’re seeking illness biomarkers or don’t expect or care about a lot of cellular heterogeneity in your sample; however, scRNA-seq is more beneficial when dealing with heterogeneity as it is able to capture expression at the cellular level.

Allogeneic stem cell transplant and aGVHD:

In allogeneic stem cell transplant, healthy blood stem cells from a donor are used to replace the recipient’s diseased or damaged bone marrow. Acute graft versus host disease (aGVHD) is a common condition that arises in 30-40% of the patients that undergo allogeneic stem cell transplants. It occurs when donor cells (graft) attack the organs and tissues of the patient who received them (host).

Differentiation pathways in human T_reg cells:

The research team from China resolved subpopulations of heterogeneous T_reg cells and analyzed Treg cells in peripheral blood (PB) and bone marrow (BM) from healthy donors and Allo-HSCT patients with or without acute GVHD (aGVHD). Using pseudo time analysis, they were able to observe two effector differentiation pathways (termed Path I and II) in both PB and BM. They also identified the signature genes for Pre-branch (such as TCF7, EEF1B2, C1orf162, and SNHG7), Path I (such as PTPRC, DDX17, MALAT1, and PDE3B), and Path II (such as HLA-DR, LGALS1/3, and CD74).

The path I cells had higher levels of CD25 and CTLA4 proteins, while Path II cells had higher levels of IL10 and TGF-1 proteins. The path I cells showed a greater suppressive but weaker proliferative potential in vitro than Path II and Pre-branch cells, while Path II cells had lower FOXP3 protein expression than Path I cells. They concluded that these aspects are conserved between PB and BM and between steady-state conditions and immune disturbance.

Future prospects:

Treg cell heterogeneity and differentiation, which had previously been unknown, has now been revealed. The study of T_reg cell differentiation has opened up a variety of research options in this area, ranging from determining the role of cell surface markers in differentiation to evaluating the end products. It also provides an excellent chance for researchers to better understand the mechanisms underlying T_reg cell-related disorders and to find potential therapeutic approaches.

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Reference:

1. Luo, Y., Xu, C., Wang, B. et al. Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in the human T_reg compartment. Nat Commun 12, 3913 (2021). https://doi.org/10.1038/s41467-021-24213-6

About author:

Akash Singh is a first-year master’s student of Biochemistry at Banaras Hindu University. He plans to pursue a Ph.D. in the near future. He aims to pursue research as his career and teach the young minds of the country.

Social media links: LinkedIn: https://www.linkedin.com/in/akash-singh-82b5811a2/

 Other publications of the author:

1. https://vidwaanforever.com/2021/06/a-new-period-invention-a-novel-thread-device-for-uti-detection/
2. https://vidwaanforever.com/2021/06/the-fall-of-insecta-apocalyptic-consequences-for-humanitys-survival/

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