Memory CD8 T cells are critical for long-lasting immunity, vaccine efficacy, and immunotherapies, but the factors controlling their differentiation are incompletely understood. Death-association protein-like 1 (Dapl1) is heterogeneously expressed in naive T cells and cytotoxic T lymphocytes (CTLs). Dapl1+ CTLs are biased to become memory cells, revealing a novel pathway for memory T cell generation. Studying molecular mechanisms which regulate development of Dapl1+ cells could elucidate processes behind memory differentiation. 

Type 1 interferons and IL-12 are cytokines that support differentiation of short-lived effector cells by augmenting Tbet expression in CD8 T cells. Since they promote the effector phenotype rather than memory, we hypothesize that cytokine-mediated Tbet expression during T cell activation decreases the frequency of Dapl1+ cells, therefore limiting memory differentiation. 

To test this hypothesis, CD8 T cells were stimulated with plate-bound antibodies or irradiated splenocytes in the presence of IFNb or IL-12. Frequency of Dapl1+ cells and phenotypes of day 5 CTLs were analyzed by flow cytometry using a Dapl1-reporter mouse model and in-house-made antibodies. As predicted, both cytokines markedly decreased the frequency of Dapl1+ CTLs. Using CD62L as a marker for a memory-like phenotype, we observed that the frequency of CD62L+ cells also decreased. Unexpectedly, Tbet overexpression in CD8 T cells did not substantially decrease Dapl1+ cells, and had no impact on memory-like T cells. Therefore, exposure to IFNb and IL-12 during activation impairs memory formation by suppressing the differentiation of Dapl1+ cells in a Tbet-independent manner. These results can inform future vaccine development against viral infections.