Two Origins of Regulatory T Cells Discovered
A new study led by Children’s Hospital of Philadelphia (CHOP) reveals that a regulatory class of human T cells comes from two different origins: one that relates to autoimmunity and one that relates to protective immunity. Published in Science Immunology, the findings could pave the way for new treatments for autoimmune diseases that target the immune system selectively.
Autoimmunity and Protective Immunity
When the immune system attacks healthy tissues, it causes autoimmune diseases. Protecting the body from infections and diseases requires robust immunity. Earlier, scientists believed that all T cells were of the same origin, so suppressing the immune system broadly was the only solution to treat inflammation caused by autoimmunity.
According to senior author Neil D. Romberg, suppressing the immune system broadly is not the only way to stop inflammation caused by autoimmunity. He explains that if all T cells come from the same place, then it is true. However, the study shows that there are two different T cell lineages, which means that suppressing inflammation caused by autoimmunity while allowing T cells that fight infection to thrive is possible.
T Follicular Regulatory (Tfr) Cells and Germinal Centers (GCs)
T follicular regulatory (Tfr) cells that function within germinal centers (GCs) are responsible for immunologic health. Their dysfunction could potentially contribute to various disease states. However, few studies have assessed the biologic roles of human Tfr cells and none have addressed where they come from or how they develop within tissues.
The researchers employed a diverse array of techniques, including computational, in vitro, and in vivo methods, to elucidate the origins, functions, and locations of Tfr cells within GCs and ultimately address this problem. They analyzed tonsils that had been removed from healthy donor patients since GCs are located in secondary lymphoid tissues like lymph nodes, spleens, and tonsils.
Two Subpopulations of Tfr Cells
The researchers were able to show that there are two subpopulations of Tfr cells: one subpopulation induced by T follicular helper (Tfh) cells, called iTfrs, and another subpopulation derived naturally from Tregs, called nTfrs. They demonstrated that there are two developmental trajectories: Treg-to-nTfr and Tfh-to-iTfr.
Different Expression of Surface Protein CD38
The researchers analyzed 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 were also able to catalogue the precise location of these different subpopulations within the GCs, in addition to demonstrating their developmental path and ability to support B cell function.
Selective Depletion of iTfr Cells
Dr. Romberg suggests that the study raises the question of whether we could selectively deplete iTfr cells through anti-CD38 treatments, while leaving nTfrs intact, using a silver bullet rather than a bomb to target specific T cells. This approach could potentially be used in a therapeutic context to boost immunity in patients with weakened immune systems.