The common belief regarding autoimmunity is that the only method of inhibiting inflammation is to broadly suppress the immune system, which may render patients more vulnerable to infections.
The researchers of this latest study have unveiled a crucial mechanism that could enable the suppression of autoantibodies while preserving immune protection.
According to a recent study by the Children’s Hospital of Philadelphia (CHOP), a regulatory subset of human T cells has two distinct origins, one associated with autoimmunity and the other with protective immunity. The study, published in Science Immunology, suggests that targeting the immune system selectively could lead to novel treatments for autoimmune disorders.
Traditionally, the accepted approach to tackling autoimmunity has been to broadly suppress the immune system to control inflammation. However, this method often leaves patients vulnerable to infections.
“However, that is only true if all T cells come from the same place,” remarks senior author Neil D. Romberg.
However, according to this study, two distinct T cell lineages exist, which opens up the possibility of simultaneously suppressing autoimmunity-induced inflammation and promoting the growth of infection-fighting T cells. This means that one can potentially achieve the desired outcome without having to compromise on either front.
Germinal centers (GCs) are circular clusters of cells found in the tonsils, lymph nodes, and spleen, which facilitate interactions between T follicular helper (Tfh) cells and B cells. The activities of these GCs are locally regulated by FOXP3+ T follicular regulatory (Tfr) cells. Although the proper functioning of Tfr cells is likely critical to maintaining immune health, and their dysfunction could contribute to various disease states, there have been few studies examining the biological roles of human Tfr cells. Furthermore, there has been no research into where they originate from or how they develop within tissues.
To address this gap, a team of researchers led by Carole Le Coz, PhD, formerly a postdoctoral researcher in the Romberg Lab, utilized a combination of computational, in vitro, and in vivo techniques to investigate the origins, functions, and locations of Tfr cells within GCs. As GCs are situated in secondary lymphoid tissues such as lymph nodes, spleens, and tonsils, the team analyzed tonsil samples obtained from healthy donors.
The researchers utilized a comprehensive set of single cell technologies to reveal that there are two distinct subpopulations of Tfr cells. One subpopulation, which they termed iTfrs, is induced by Tfh cells, while the other subpopulation, which they named nTfrs, is naturally derived from Tregs, a T cell subpopulation responsible for regulating the immune system. Consequently, two developmental pathways were identified: Treg-to-nTfr and Tfh-to-iTfr.
Following the identification of these two Tfr cell subpopulations, the researchers analyzed whether the two regulatory T cells expressed the CD38 surface protein differently. Their findings revealed that iTfr cells expressed CD38, whereas nTfr cells did not. Additionally, the researchers precisely located these distinct Tfr subpopulations within the GCs, and demonstrated their developmental trajectory and capacity to support B cell function.
The findings raise “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,” Dr. Romberg adds. “A similar approach could also potentially be used in a therapeutic context to boost immunity in patients with weakened immune systems.”
Source: 10.1126/sciimmunol.ade8162
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