Requirement for T-bet in the aberrant differentiation of unhelped memory CD8⁺ T cells

Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8⁺ T cells and self-renewal of central–memory CD8⁺ T cells. We now show that T-bet represses transcription of IL-7Rα and drives differentiation of effector and effector–memory CD8⁺ T cells at the expense of central–memory cells. We also found T-bet to be overexpressed in CD8⁺ T cells that differentiated in the absence of CD4⁺ T cell help, a condition that is associated with defective central–memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of “unhelped” memory CD8⁺ T cells. T-bet, thus, appears to function as a molecular switch between central– and effector–memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8⁺ T cells.