Reprogramming immune cells to repair tissue damage

The immune system’s main function is to defend the body against infections or cancer. In recent years, investigations in mice revealed that immune cells also have the important role of supporting the healing of damaged tissues and of maintaining the normal function of healthy tissues. One type of immune cells with particularly strong tissue-regenerative features are the regulatory T (T_reg) cells. Former studies in mice have revealed an important role of these cells in promoting tissue regeneration in virus induced lung damage, stroke, colitis, muscle repair and metabolic disorders. However, it remained so far unclear whether the human immune system has comparable capacities. Scientists at the Regensburg Center for Interventional Immunology (RCI) have now identified and characterized human tissue-regenerative T_reg cells. They also developed a manufacturing method to generate these cells in the lab, opening up the possibility of using these cells for regenerative medicine. These findings are now published in the journal Immunity.

Michael Delacher, Ph.D. and Markus Feuerer, M.D, from the RCI built on their previous studies in which they described tissue-regenerative T_reg cells in mice^[1], [2] and elucidated their developmental pathway^[3].

Cells determine all their features and functions through “on” and “off” switches that are distributed over the entire genome and regulate the activity of each gene. Together these form an “epigenetic fingerprint” which is highly specific for a particular cell type. By comparing the epigenetic fingerprints of tissue resident T_reg cells in humans and mice the scientists identified a species-conserved tissue-regenerative T_reg signature. “This epigenetic signature combined with gene expression profiling enabled us to pinpoint the exact nature of human tissue-regenerative T_reg cells.” said Delacher. “We found that tissue-regenerative T_reg cells share several features with another type of T cells – the so-called T follicular helper (T_fh)- a cell subset that orchestrates the production of antibodies.” noted Malte Simon, a bioinformatician from the German Cancer Research Center, who was involved in bioinformatic analysis of this study. This observation turned out to be critical for the development of a manufacturing protocol for tissue-regenerative T_reg cells. “Since culture conditions promoting the generation of T_fh-like cells were previously known, we adopted them for the manufacturing of tissue-regenerative T_reg cells”, said Lieke Sanderink, a PhD student at the RCI involved in the programming of T_reg cells.

On this basis, the RCI scientists plan to design specific cell therapies employing tissue-regenerative T_reg cells for regenerative medicine. “We might be able to use these cells to repair tissue damage after bone marrow transplantation, a treatment to combat leukemia and other blood cancers” said Feuerer.

A dark side of tissue-regenerative T_reg cells is their support of tumor growth. “Once we better understand how these cells activate their functions we may be able to inhibit their counterproductive effects in tumors to enhance the success of cancer treatment” said Philipp Beckhove, the RCI scientific director. 

References:

^{[1] Delacher M, et al. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nature Immunology, 2017; 18(10):1160-1172
[2] Delacher M, et al. RBPJ expression in regulatory T cells is critical for restraining TH2 responses. Nature Communications, 2019; 10(1):1621
[3] Delacher M, et al. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity, 2020; 18;52(2):295-312} 

Source: University Hospital Regensburg

01.04.2021

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