Memory CD8⁺ T Cells Co-expressing TCF1 and ID2 Combine Effector and Stem-like Functions in Persistent Infections

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Abstract
ID2 expression is typically associated with promoting effector differentiation in CD8⁺ T cells. Here, we show that ID2 upregulation instead characterizes the optimal memory CD8⁺ T cell response in individuals who naturally maintain durable control of HIV-1 without therapy. We further identify a subset of memory CD8+ T cells co-expressing the transcription regulators TCF1 and ID2 that combine stemness with broad effector functions. These TCF1+ID2+ cells exhibit high proliferative capacity, robust cytokine production, and restrained expression of exhaustion markers, enabling sustained responses upon repeated antigen stimulation. They constitute the predominant virus-specific memory CD8+ T cell population in naturally controlled CMV, HIV-1, and SIV infections. Our findings reveal a poised memory state that balances effector and survival programs, suggesting that TCF1+ID2+ memory CD8+ T cells play a central role in maintaining durable antiviral immunity during persistent infections.

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