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Cell Rep. 2023 Mar 28;42(3):112195. doi: 10.1016/j.celrep.2023.112195
Wenqiang Cao 1, Ines Sturmlechner 2, Huimin Zhang 3, Jun Jin 3, Bin Hu 4, Rohit R Jadhav 3, Fengqin Fang 5, Cornelia M Weyand 6, Jörg J Goronzy 7
Affiliations expand
- PMID: 36884349
- PMCID: PMC10118747
- DOI: 10.1016/j.celrep.2023.112195
Free PMC article
Abstract
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.