Transforming dysfunctional CD8⁺ T cells into natural controller–like CD8⁺ T cells: can TCF-1 be the magic wand?

HIV infection results in defective CD8⁺ T cell functions that are incompletely resolved by antiretroviral therapy (ART) except in natural controllers, who have functional CD8⁺ T cells associated with viral control. In this issue of the JCI, Perdomo-Celis et al. demonstrated that targeting the Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) pathway in dysfunctional CD8⁺ T cells led to gains in stemness phenotype, metabolic quiescence, survival potential, response to homeostatic γ-chain cytokines, and antiviral capacities, similar to profiles of functional CD8⁺ T cells in natural controllers. Although reprogramming might not sufficiently reverse the imprinted dysfunction of CD8⁺ T cells in HIV infection, these findings outline the Wnt/TCF-1 pathway as a potential target to reprogram dysfunctional CD8⁺ T cells in efforts to achieve HIV remission.