This story on regulatory T cell function and its therapeutic potential falls within a greater series on regenerative medicine.

In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

One study published in Science discovers fascinating characteristics of oft-overlooked white blood cells in the lymph nodes, a memory-like regulatory T cell that is likely critical to maintaining local immune surveillance and helps the body distinguish its own cells from its enemies. This is an important finding for developing new therapies that take advantage of immune cell function and apply this knowledge to heal. On the other hand, this finding also underscores a potential danger for immunotherapies that ablate or downregulate these white blood cells: the loss of self-tolerance.

All About Regulatory T Cells

Regulatory T cells, also known as Tregs, are a specialized subset of white blood cells that protect the body’s immune balance. When the immune system produces excessive, misdirected and potentially dangerous responses to pathogens, regulatory T cells prevent damage by suppressing or regulating the activity of the immune cells responsible. Without this protective mechanism, the body may mistakenly recognize its own cells as a threat and attack, leading to autoimmune diseases, allergies and chronic inflammation.

While many cell-based therapies prefer the cytotoxic power of killer T cells (e.g., CAR T therapy), recent research suggests it can be beneficial to modulate immune responses via regulatory T cells. For example, work from the Bert O’Malley lab demonstrated that inhibiting a key protein in regulatory T cells can increase the number of infiltrating cytotoxic immune cells in mouse breast tumors and significantly suppress tumor growth. Building upon this discovery, the team then knocked out this protein gene in mice. Mice without the knockout display rapid tumor growth after receiving an injection of cancer cells. In comparison, the breast tumors in the knockout mice were undetectable 20 days after injection and did not return, underscoring the potential of manipulating regulatory T cells to treat cancer.

New Discovery: Memory-like Treg Properties  

Grasping the dynamics and functions of Tregs is essential for developing targeted immunotherapies and strategies to modulate the immune system effectively. To this end, researchers at the RWTH Aachen University in Germany sought to understand more about regulatory T cell characteristics. Through a series of experiments, the team discovers that certain Tregs possess a memory-like phenotype that could provide specific and local suppression of immune responses in draining lymph nodes. This finding could provide therapeutic opportunities for addressing chronic inflammatory diseases locally rather than systemically.

Memory in the Lymph Nodes 

It is first important to underscore current understandings of the lymph nodes and their role in immune cell migration/function. The lymph nodes are small, bean-shaped tissues distributed throughout the body’s lymphatic system. They drain and filter lymphatic fluid to remove foreign particles, antigens and damaged cells. Immune cells congregate in these organs and become exposed to all these various antigens. This exposure contributes to immune cell maturation and helps the white blood cells concert immune responses. Some white blood cells remain in the lymph nodes long-term, establishing a “resident” population of memory cells that retain a local memory of past immune events and can influence nearby immune responses for extended periods of time.

Regulatory T cells are not traditionally considered resident in the lymph nodes. In fact, conventional knowledge suggests that Tregs are resident in nonlymphoid tissues such as the skin, lungs and gut, and only circulate through the lymph nodes. Could this really be the case?

The researchers at RWTH Aachen University turned to photoconvertible protein labeling to track the turnover rates of regulatory T cells in mice lymph nodes. They monitored the migration of Tregs from gut-draining mesenteric lymph nodes and from skin-draining peripheral lymph nodes. This in vivo monitoring revealed that, indeed, the majority of Tregs in the lymph nodes recirculate the body. However, 10 to 20% of the regulatory T cells remain in their respective lymph nodes for weeks to months. This persistence of Treg cells could point to their long-term involvement in local immune regulation.

The team then analyzed the gene expression patterns of these memory-like Treg cells using single-cell RNA sequencing. The gene clusters suggested that these T cells are highly varied in function and origin. Fascinatingly, they also share core residency gene signatures with typically resident cells, such as killer T cells. Considering these shared characteristics, Treg cells very likely join conventional resident immune cells in the lymph nodes in maintaining local immune homeostasis. This finding could be wielded to develop therapies that target multiple immune cell populations—Tregs, killer T cells and conventional helper T cells—at once.

Compared to circulating regulatory T cells, the memory-like Tregs in the lymph nodes exhibit a unique set of T cell receptor expression. A transfer experiment showed that resident Treg clones reacquire their memory-like phenotype in their lymph nodes of origin. Likely, the unique regulatory T cells’ role corresponds to the local antigen pool found in each different lymph node.

Altogether, these discoveries challenge the long-standing belief that regulatory T cells in the lymph nodes are homogeneous with recirculating properties.

Potential Danger: Losing Self-Tolerance 

Manipulating regulatory T cell activity could provide substantial therapeutic benefits, but researchers must tread carefully. These results suggest that downregulating Treg expression could wipe out the body’s self-tolerance. Self-tolerance describes the immune system’s ability to recognize its own cells as non-threats while mounting appropriate responses to foreign substances/pathogens. This mechanism is critical to prevent the immune system from attacking the body’s own tissues. Losing self-tolerance leads to autoimmune and chronic inflammatory diseases such as type-1 diabetes, inflammatory bowel disease, and multiple sclerosis.

Research Implications 

Regulatory T cells play a distinct role in the immune system by orchestrating immune balance. While perhaps less known than other T cell subsets such as killer T cells, these cells hold promise for treating a wide variety of illnesses. The study by RWTH Aachen University researchers highlights this potential. They illustrate that a minority of Tregs can persist locally in the lymph nodes, influencing immune responses for extended periods. This knowledge, if manipulated carefully, offers the potential to address chronic inflammatory diseases precisely and locally. A future installment will expand upon regulatory T cell research and the use of Cre-loxP, an experimental system that new research suggests may have unforeseen limitations.