Definition of a murine CD8+ MHCII-recognizing effector T cell population

Abstract

CD4+ and CD8+ T cells are dichotomous lineages in adaptive immunity. While conventionally viewed as distinct fates that are fixed post-thymic development, accumulating evidence indicates that these two populations can exhibit significant lineage plasticity, particularly upon TCR-mediated activation. In this work, I define a novel murine CD4-CD8ab+ MHCII-recognizing population generated from effector CD4+ T cells. Effector CD4-CD8ab+ MHCII-recognizing T cells downregulate expression of T helper cell-associated costimulatory molecules and increase expression of cytotoxic T lymphocyte-associated cytotoxic molecules. TCRb repertoire sequencing and in vivo genetic lineage tracing in acutely-infected wild-type mice demonstrate fundamental lineage reprogramming resulting in an “ex-CD4” T cell phenotype, rather than expansion of an aberrantly-developed CD8+ MHCII-restricted population. Impairing autophagy by functional deletion of the initiating kinase Vps34 or a downstream enzyme Atg7 dramatically enhances the generation of effector CD4-CD8ab+ MHCII-recognizing T cells. These findings suggest that effector CD4+ T cells can exhibit a previously unreported degree of skewing towards the CD8+ T cell lineage, which may point towards a novel direction for vaccine design, particularly against HIV.