Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes

Idan Hekselman ^3,4,7 Yehezqel Elyahu ^1,2,3,7 Inbal Eizenberg-Magar ⁵ Omer Berner ^1,2,3 Itai Strominger ^1,2,3 Maya Schiller ⁶ Kritika Mittal ^1,2,3 Anna Nemirovsky ^1,2,3 Ekaterina Eremenko ^1,2,3 Assaf Vital ^3,4 Eyal Simonovsky ^3,4 Vered Chalifa-Caspi ³ Nir Friedman ⁵ Esti Yeger-Lotem ^3,4 Alon Monsonego ^1,2,3

¹The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
²Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Israel
³National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Israel
⁴Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
⁵Department of Immunology, Weizmann Institute of Science, Israel
⁶Departments of Immunology and Neuroscience, Rappaport Faculty of Medicine, and the Integrated Cancer Center, Technion-Israel Institute of Technology, Israel
⁷Note, these authors contributed equally to this work

Age-associated changes in CD4 T-cell functionality have been linked to chronic inflammation and decreased immunity. However, a detailed characterization of CD4 T cell phenotypes that could explain these dysregulated functional properties is lacking. In our study, which was published in Science Advances, we used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of CD4 T cells obtained from young and old mice. We found that the landscape of CD4 T cell subsets differs markedly between young and old mice, such that three cell subsets—exhausted, cytotoxic, and activated regulatory T cells (aTregs)—appear rarely in young mice but gradually accumulate with age. Most unexpected were the extreme pro- and anti-inflammatory phenotypes of cytotoxic CD4 T cells and aTregs, respectively. These findings provide a comprehensive view of the dynamic reorganization of the CD4 T cell milieu with age and illuminate dominant subsets associated with chronic inflammation and immunity decline, suggesting new therapeutic avenues for age-related diseases.