CD4 T cell memory is impaired by species-specific cytotoxic differentiation, but not by TCF-1 loss.

CD4 T cells are typically considered as 'helper' or 'regulatory' populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4 cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4 CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4 CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4 CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4 CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of , which encodes TCF-1, at the time of CD4 T cell activation, we further show that, contrary to observations in CD8 T cells, continued expression of TCF-1 is not required for CD4 T cell memory survival. Whilst -deficient CD4 T cells persisted normally following retroviral infection, the CD4 CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4 CTL survival. Using xenotransplantation of human CD4 T cells into murine recipients, we demonstrate that human CD4 CTLs develop and persist in the same experimental conditions where murine CD4 CTLs fail to persist. These observations uncover a species-specific defect in murine CD4 CTL persistence with implications for their use as a model system.