The role of DCAF1-GSTP1-ROS axis in regulating T cell senescence in immunological ageing and tumors

Abstract

Abstract Immunological aging is characterized by chronic nonspecific inflammation, compromised vaccination and declined immune competence, contributing many age-associated diseases. As the central regulator of immune system, whether and how regulatory T (Treg) cells are regulated during ageing are not fully understood due to a lack of specific markers. By a combination of cellular, molecular and bioinformatic approaches, we discovered that Treg cells senesce more severely than conventional T (Tconv) cells during ageing. Treg cells from aged mice were less efficient than young Treg cells to suppress Tconv cell function in an inflammatory-bowel-disease model and to prevent Tconv cell ageing in the irradiation-induced ageing model. Further study revealed that DCAF1 (DDB1 and CUL4 associated factor 1) was downregulated in aged Treg cells and was critical to restrain Treg cell ageing via glutathione S-transferase P (GSTP1) regulated reactive-oxygen-species (ROS). Functionally, interfering with GSTP1 and ROS pathways reinvigorated the proliferation and function of aged Treg cells. Thus, the DCAF1-GSTP1 regulated ROS contributes to Treg cell senescence, which led to systemic immunological ageing. In tumor microenvironment, ROS produced by Treg cells and myeloid-derived suppressive cells (MDSCs) is one of the major inhibitory molecules suppressing anti-tumor immunity. We found that there was significant increase of senescent T cells in tumors in a B16 melanoma model, featured with increased p16 expression, elevated senescence associated β-gal activity and increased KLRG1 expression. Further investigating the role of DCAF1-GSTP1-ROS axis in tumor infiltrating T cells will provide novel mechanistic insights to cancer immunotherapy.