ITK tunes IL-4-induced development of innate memory CD8⁺ T cells in a γδ T and invariant NKT cell-independent manner

True memory CD8⁺+ T cells develop post antigenic exposure and can provide life-long immune protection. More recently, other types of memory CD8⁺+ T cells have been described, such as the memory-like CD8⁺ T cells (IMP; CD44^hiCD122⁺) that arise spontaneously in Itk^-/- mice, which are suggested to develop as a result of IL-4 secreted by NKT-like γδ T or PLZF⁺ NKT cells found in Itk^-/- mice. However, we report here that whereas IMP CD8⁺ T cell development in Itk^-/- mice is dependent on IL-4/STAT6 signaling, it is not dependent on any γδ T or iNKT cells. Our experiments suggest that the IMP develops as a result of tuning of the CD8⁺ T cell response to exogenous IL-4 and TCR triggering by ITK and challenge the current model of IMP CD8⁺ T cell development as a result of NKT-like γδ T or iNKT cells. These findings suggest that some naive CD8⁺ T cells may be preprogrammed by weak homeostatic TCR signals in the presence of IL-4 to become memory phenotype cells with the ability to elaborate effector function rapidly. The role of ITK in this process suggests a mechanism by which IMP CD8⁺ T cells can be generated rapidly in response to infection.