Two Classes of Regulatory T Cells, with Therapeutic Implications Identified
A study by Children’s Hospital of Philadelphia (CHOP) researchers has found that a class of human regulatory T cells descends from two different origins, one that relates to autoimmunity and one that relates to protective immunity. The discovery, they suggest, could pave the way for new treatments for autoimmune diseases that target these different subsets of immune system T follicular regulatory (Tfr) cells selectively.
“When it comes to autoimmunity, the prevailing wisdom has been that the only way to stop inflammation is to suppress the immune system broadly, making patients more susceptible to infection,” said Neil D. Romberg, MD, an attending physician in the division of allergy and immunology at CHOP. “However, that is only true if all T cells come from the same place. What this study shows is that there are two different T cell lineages, which means you might be able to have your cake and eat it too—suppressing inflammation due to autoimmunity while allowing T cells that fight infection to thrive.”
Romberg is senior author of the team’s published paper in Science Immunology, which is titled, “Human T follicular helper clones seed the germinal center-resident regulatory pool,” in which they concluded: “Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.”
Germinal centers (GCs) are spherical collections of cells inside tonsils, lymph nodes, and the spleen, which orchestrate interactions between T follicular helper (Tfh) cells and B cells. The action within these GCs is locally governed by FOXP3+ Tfr cells. “GCs are remotely controlled by negative feedback from their primary product, systemically circulating affinity-maturated antibodies, and locally governed by FOXP3+ Tfr cells,” the authors explained.
Although the proper function of Tfr cells is likely important to immunologic health—and their dysfunction a potential contributor to various disease states—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. “Although their proper function is likely important to immunologic health and their dysfunction a potential contributor to various disease states, few studies have assessed the origins of human Tfr cells, their intermediate development stages, or their biological functions within tissues,” the team noted. “The mechanisms by which FOXP3+ Tfr cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood.”
For their reported study the researchers, led by Carole Le Coz, PhD, a former postdoctoral researcher in the Romberg Lab, used a combination of computational, in vitro, and in vivo techniques to describe the origins, functions, and positions of Tfr cells within GCs. Since GCs are located in secondary lymphoid tissues, such as lymph nodes, spleen, and tonsils, the researchers analyzed tonsils that had been removed from healthy donor patients.
Using an interlocking suite of single cell technologies, the researchers were able to show that there is one subpopulation of Tfr cells—iTfr cells—that is induced by Tfh cells, and another subpopulation (nTfr) that is naturally derived from Tregs, a subpopulation of T cells that are responsible for moderating the immune system. So their results demonstrated that there are two developmental trajectories: Treg-to-nTfr and Tfh-to-iTfr.
Having identified these two subpopulations of Tfr cells, the investigators then evaluated scRNA-seq data to look for differential gene expression (DEG) between the two types of regulatory T cells. Most notably they found that iTfr cells expressed CD38, whereas nTfr cells do not. “Of all DEGs encoding cell surface proteins, CD38 was among the most promising candidates to potentially distinguish iTfr from nTfr cells,” they wrote. They were also able to catalog the precise location of these different subpopulations within the GCs, in addition to demonstrating their developmental path and ability to support B cell function. “Our results identify human iTfr cells as a distinct CD38+, germinal center–resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38−nTfr cells are elite suppressors primarily localized in follicular mantles,” they wrote.
“This 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,” Romberg said. “A similar approach could also potentially be used in a therapeutic context to boost immunity in patients with weakened immune systems.”
https://www.genengnews.com/autoimmune-disorders/study-identifies-two-classes-of-regulatory-t-cells-with-therapeutic-implications/#:~:text=Two%20Classes%20of%20Regulatory%20T%20Cells%2C%20with%20Therapeutic%20Implications%20Identified,-April%2010%2C%202023&text=A%20study%20by%20Children's%20Hospital,that%20relates%20to%20protective%20immunity.
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