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Aging Tregs need DCAFinating

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Science Immunology  02 Oct 2020:
Vol. 5, Issue 52, eabe9581
DOI: 10.1126/sciimmunol.abe9581

Abstract

Loss of DCAF1 and resulting ROS leads to Treg aging and inflammation.

Growing evidence has indicated that the increased incidence of comorbidities in age-related diseases, such as rheumatoid arthritis and Alzheimer's disease, are mainly due to disrupted immune homeostasis. Regulatory T cells (Tregs) play a critical role in maintaining the balance of the immune system. In these studies, Guo and colleagues show that Tregs from aged mice exhibit several markers of immune senescence and function poorly when compared to Tregs from young mice. Older Tregs have both diminished proliferative capacity and are unable to control inflammation that occurs both with advanced age (inflammaging) and in an irradiation-induced immune-aging model.

In their investigation of mechanisms underlying the Treg aging phenotype, the authors identify the E3 ubiquitinase DCAF1 (DBB1 and CUL4 associated factor 1) as a critical factor. DCAF1 expression is decreased both with normal aging and in the setting of HIV infection, a situation known to induce inflammaging. DCAF1 was shown to mono-ubiquitinate GSTP1 (glutathione S-transferase P), suppressing ROS (reactive oxygen species) activity. Loss of DCAF1 by normal aging, conditional gene deletion in murine Treg, or gene knockdown in human Treg leads to increased ROS as well as gene expression-based evidence of aging and dysfunctional Tregs. Interestingly, elimination of excessive ROS by treating Tregs with ROS scavengers such as NAC (N-acetyl-l-cysteine) and GSH (glutathione) can rejuvenate the aged Treg cells and reinvigorate their suppressive function. Taken together, these findings suggest that DCAF-regulated ROS is the culprit underlying Treg cell aging and aberrant function in immune senescence and inflammaging. Further investigations of DCAF1 or other ROS negative regulators may provide deeper insight into inflammaging and have implications in chronic infectious disease such as HIV, age-related immune disease, and in the growing field of adoptive Treg therapy.

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