The human immune system is a complex network of cells and molecules that work together to defend the body against harmful pathogens. Within this network, regulatory T cells play a crucial role in maintaining immune homeostasis by suppressing excessive immune responses to prevent damage to healthy tissues. In a recent study published in Science, researchers have discovered that regulatory T cell populations in mice can arise from two distinct developmental origins. This finding sheds new light on the complexity of the immune system and has important implications for the development of novel therapies for autoimmune diseases and cancer.
A new study led by Children’s Hospital of Philadelphia (CHOP) has found that a regulatory class of human T cells stems from two different origins: one relating to autoimmunity, and one to protective immunity. This research, published in Science Immunology, could lead to new treatments that focus on the immune system selectively to address autoimmune diseases.
Traditionally, the understanding has been that suppressing the entire immune system is the only way to stop inflammation resulting from autoimmunity. However, if both of the two T cell lineages can be identified and studied, it may be possible to suppress inflammation while still allowing T cells that fight infection to thrive.
Germinal centers (GCs) are groups of cells inside tonsils, lymph nodes, and the spleen that oversee interactions between T follicular helper (Tfh) cells and B cells. Local action in these GCs is regulated through FOXP3+ T follicular regulatory (Tfr) cells. Though Tfr cells are likely vital to immunologic health and their malfunction can contribute to various disease states, few studies have explored the biologic roles of human Tfr cells or how they develop within tissues.
To learn more, researchers at the Romberg Lab used a combination of computational, in vitro, and in vivo techniques to determine the origins, functions, and positions of Tfr cells within GCs. Since GCs are situated in secondary lymphoid tissues like lymph nodes, spleens, and tonsils, the team analyzed tonsils removed from healthy donors.
Using a suite of single-cell technologies, the researchers identified one subpopulation of Tfr cells induced by Tfh cells, called iTfrs, and another subpopulation that is naturally derived from Tregs: subpopulations of T cells that regulate the immune system, called nTfrs. In doing so, the study revealed two developmental trajectories: Treg-to-nTfr and Tfh-to-iTfr.
The scientists then assessed whether these two regulatory T cells express the surface protein CD38 differently. They found that iTfr cells express CD38, whereas nTfr cells do not. They also catalogued the different subpopulations’ precise location within the GCs, demonstrating their developmental path and their B cell function support.
Dr. Romberg believes that the study raises the question of whether iTfr cells could be selectively depleted through anti-CD38 treatments while sparing nTfrs. Such an approach could be used therapeutically to enhance immunity in those with weakened immune systems.
As we have seen in this article, regulatory T cell populations are essential for maintaining immune system balance and preventing autoimmune diseases. However, recent research has revealed that these cells have not one, but two distinct origins. This finding sheds new light on the complexity of the immune system and highlights the importance of understanding the different mechanisms involved in the development and function of regulatory T cells. With this knowledge, scientists can continue to identify new therapeutic targets for a range of immune-related conditions. It is exciting to think about the doors that may open through further exploration of regulatory T cell populations and their potential to unlock new treatments for a variety of diseases.
