TRIB2 safeguards naive T cell homeostasis during aging
Wenqiang Cao,
Ines Sturmlechner,
Huimin Zhang,
Jun Jin,
Bin Hu,
Rohit R. Jadhav,
Fengqin Fang,
Cornelia M. Weyand,
Jörg J. Goronzy
Affiliations
Wenqiang Cao
Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China; Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Corresponding author
Ines Sturmlechner
Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
Huimin Zhang
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
Jun Jin
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
Bin Hu
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA
Rohit R. Jadhav
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
Fengqin Fang
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
Cornelia M. Weyand
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Medicine, Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
Jörg J. Goronzy
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Palo Alto Veterans Administration Healthcare System, Palo Alto, CA 94305, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Medicine, Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Corresponding author
Summary: Naive CD4+ T cells are more resistant to age-related loss than naive CD8+ T cells, suggesting mechanisms that preferentially protect naive CD4+ T cells during aging. Here, we show that TRIB2 is more abundant in naive CD4+ than CD8+ T cells and counteracts quiescence exit by suppressing AKT activation. TRIB2 deficiency increases AKT activity and accelerates proliferation and differentiation in response to interleukin-7 (IL-7) in humans and during lymphopenia in mice. TRIB2 transcription is controlled by the lineage-determining transcription factors ThPOK and RUNX3. Ablation of Zbtb7b (encoding ThPOK) and Cbfb (obligatory RUNT cofactor) attenuates the difference in lymphopenia-induced proliferation between naive CD4+ and CD8+ cells. In older adults, ThPOK and TRIB2 expression wanes in naive CD4+ T cells, causing loss of naivety. These findings assign TRIB2 a key role in regulating T cell homeostasis and provide a model to explain the lesser resilience of CD8+ T cells to undergo changes with age.
