TRIB2 safeguards naive T cell homeostasis during aging

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.