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

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

¹National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Israel
²Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Israel
³The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Israel
⁴Zlotowski Neuroscience Center and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Israel
⁵Department of Immunology, Weizmann Institute of Science, Israel
⁶Department of Immunology and Neuroscience, Technion-Israel Institute of Technology, Israel

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 a study published in Science Advances 2019, 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 (aT_regs)-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 aT_regs, 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.