Ex-T Regulatory Cells Contribute to the Inflammation Driving Atherosclerosis

Researchers here report on their investigation of a problem T cell subpopulation in the context of atherosclerosis and the inflammation that is characteristic of that condition. These T cells appear to be maladapted forms of regulatory T cell, gone rogue and producing harmful inflammatory signaling in response to the environment of an atherosclerotic plaque. There is considerable interest in finding approaches to modulate immune activity to dampen the pace at which atherosclerotic plaques come into being and grow, though much of this centers on the role of the innate immune cells known as macrophages. Once inflammation gets underway, however, any and all immune cells might be drawn in to become involved in ways that contribute to pathology, as this research illustrates.

T regulatory cells (Tregs) have the important job of stopping the other T cells from releasing too many inflammatory, or cytotoxic, molecules as they fight infection. Some T cells contribute to atherosclerosis by attacking a molecule called apolipoprotein B (APOB), the main component in the "bad" cholesterol that builds up into dangerous plaques in the arteries. These T cells ramp up their attacks as atherosclerosis worsens, likely adding to inflammation in the arteries. The weird thing is that these T cells look a lot like the normally helpful Tregs. A new study reveals the true identities of these cells: they are exTregs. ExTregs are like zombie Tregs. They've gone through a genetic "deprogramming" and lost their ability to help regulate inflammation. Scientists don't know exactly why exTregs develop, but the phenomenon may happen when the body misses the mark in an attempt to adapt to chronic disease.

Researchers tagged both Tregs and harmful exTregs in a mouse model prone to atherosclerosis. These fluorescent red and green tags glowed when Tregs were functioning normally. A switch from green and red to only red revealed exTreg development in real time. The team then took organ samples from the mice and used a technique called flow cytometry to detect the green and red tags to sort the Tregs from the exTregs. The researchers used techniques called bulk RNA sequencing to learn more about these cells. The sequencing highlighted vast differences in gene expression and showed that exTregs make a distinct set of genes that sets them apart from Tregs.

Next, the researchers used the exTreg markers found in mice to transpose them to a single cell RNA sequencing performed on human blood samples. Through this process, they successfully identified biomarkers for human exTregs. The researchers found that the exTreg biomarkers they'd seen in mouse samples were also relevant for human exTregs. They discovered that exTregs from humans with atherosclerosis are potentially more potent. Going forward, the researchers hope to use exTreg biomarkers to detect and study the roles of these cells in other chronic health conditions, such as in patients with autoimmune diseases. Resesearchers also interested in studying samples from the same individual patients taken over time. How might exTreg biomarkers change as atherosclerosis changes? Would they see decreased signs of exTregs if a patient was put on an effective medication?

Link: https://www.lji.org/news-events/news/post/when-regulatory-t-cells-go-bad/


Thanks for linking to the interesting publication. (direct article link here: https://www.nature.com/articles/s41590-023-01589-9)

The researchers are calling these "exTregs" - is it possible they are simply "senescent Tregs?" The upregulation of "inflammatory cytokines" and genes (Figures 6 and 7) seems very analogous to SASP, and "exTregs" do not seem to proliferate meaningfully (eg, figure 4d).

Unfortunately the researchers did not seem to perform any studies of conventional senescence markers (eg, SA-b-gal, p16, p21, SAHF); I wonder if this is simply rebranding the long-established idea of immunosenescence...

Posted by: Edward F Greenberg at August 19th, 2023 11:45 AM

As a follow-up to the above: see here detailing "novel senescent regulatory T cells" in RA patients (Fessler et al. Front Immunol 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357868/).

The cells in that paper share a number of common features with the "exTregs" mentioned in your paper:
- CD4+FoxP3+;
- Reduced CD25 vs "normal" Tregs
- proinflammatory
- less effective in "regulating" effector T cells
- low proliferation (by CFSE)

It would be nice if the "ExTreg" authors looked at the markers of senescence used in the above paper Figure 3 (eg, γH2AX, SABG, telomere lengths)

Posted by: Edward F Greenberg at August 20th, 2023 1:10 PM
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