CHOP Study Uncovers Two Unexpected Regulatory T Cell Types

A groundbreaking new study from Children’s Hospital of Philadelphia (CHOP) has revealed that a special class of human T cells, which are responsible for both autoimmune and protective immunity, have two distinct origins.

This discovery could be a major breakthrough in the development of targeted treatments for autoimmune diseases, providing a greater understanding of how to effectively combat them. The findings, published today in Science Immunology, could be a game-changer in the fight against these debilitating diseases.

The traditional approach to treating autoimmunity has been to suppress the immune system, leaving patients more vulnerable to infection. However, this study reveals that there are two distinct T cell lineages, meaning it may be possible to limit inflammation from autoimmunity while allowing T cells that protect against infection to remain active.

Senior author Neil D. Romberg, MD, an attending physician in the Division of Allergy and Immunology at Children’s Hospital of Philadelphia, believes this opens up a new pathway for treating autoimmune disorders.

Germinal centers are enigmatic structures found in tonsils, lymph nodes, and the spleen, where intricate interactions between T follicular helper (Tfh) cells and B cells take place. A key player in the regulation of this process is the FOXP3+ T follicular regulatory (Tfr) cell; however, little is known about what roles human Tfr cells serve and how they develop within tissues. Unravelling the mysteries of these GCs may provide valuable insight into the workings of immunologic health and potential links to various disease states.

In a groundbreaking study, Carole Le Coz, PhD and her colleagues from the Romberg Lab used a combination of computational, in vitro, and in vivo techniques to uncover the origins, functions, and positions of Tfr cells within GCs.

To do this, the researchers examined tonsils removed from healthy donor patients located in secondary lymphoid tissues such as lymph nodes, spleens, and tonsils. Their findings have shed new light on the intricate workings of the human immune system.

Using a combination of single cell technologies, researchers discovered two distinct subpopulations of Tfr cells with distinct developmental trajectories. The iTfrs were derived from Tfh cells, and the nTfrs were derived from Tregs, cells responsible for moderating the immune system. This finding was an important step forward in understanding the complexity of the Tfr cell population and its role in regulating the immune system.

The researchers identified two subpopulations of Tfr cells and analyzed their expression of the surface protein CD38. They discovered that iTfr cells express CD38, while nTfr cells do not.

Furthermore, they were able to map out the exact location of these distinct subpopulations within the GCs and trace their developmental path and ability to support B cell function. This novel insight into the biology of Tfr cells has opened new avenues of exploration in the field.

This study opens up the possibility of selectively depleting iTFR cells, while leaving nTFRs intact, through anti-CD38 treatments. This approach could potentially be used therapeutically to bolster immunity in patients with compromised immune systems, much like using a silver bullet to target specific T cells, instead of a bomb.

This work was made possible through generous grants from the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases (AI146026, AI155577, AI115712, AI117950, AI108545, CA210944, AI114852), the National Heart, Lung, and Blood Institute (R38 HL143613, T32 HL 7775-28), and the National Cancer Institute (T32 CA009140).

Further support came from the Parker Institute for Cancer Immunotherapy, the Parker Bridge Fellow Award, the Gray Foundation, the Chan Zuckerberg Initiative Pediatric Networks for the Human Cell Atlas, the Gail B. Slap Department of Pediatrics Fellowship Award, and the Sayer family. Thanks to these generous contributions, this work has been made possible.

About Children’s Hospital of Philadelphia:

Children’s Hospital of Philadelphia has been a beacon of hope for children in need since its founding in 1855. As the first ever pediatric hospital in the nation, its pioneering spirit has been instrumental in improving the lives of children around the world.

With its 595-bed hospital, CHOP Care Network of over 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances across Pennsylvania and New Jersey, as well as an inpatient hospital with a dedicated pediatric emergency department, its commitment to providing advanced pediatric care close to home has been unwavering.

Its long-standing dedication to exceptional patient care, training new generations of pediatric healthcare professionals, and groundbreaking research initiatives have earned CHOP the recognition of a leading advocate for children and adolescents.

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