Conversion of effector CD4⁺ T cells to a CD8⁺ MHC II-recognizing lineage

CD4⁺ and CD8⁺ T cells are dichotomous lineages in adaptive immunity. While conventionally viewed as distinct fates that are fixed after thymic development, accumulating evidence indicates that these two populations can exhibit significant lineage plasticity, particularly upon TCR-mediated activation. We define a novel CD4^-CD8αβ⁺ MHC II-recognizing population generated by lineage conversion from effector CD4⁺ T cells. CD4^-CD8αβ⁺ effector T cells downregulated the expression of T helper cell-associated costimulatory molecules and increased the expression of cytotoxic T lymphocyte-associated cytotoxic molecules. This shift in functional potential corresponded with a CD8⁺-lineage skewed transcriptional profile. TCRβ repertoire sequencing and in vivo genetic lineage tracing in acutely infected wild-type mice demonstrated that CD4^-CD8αβ⁺ effector T cells arise from fundamental lineage reprogramming of bona fide effector CD4⁺ T cells. Impairing autophagy via functional deletion of the initiating kinase Vps34 or the downstream enzyme Atg7 enhanced the generation of this cell population. 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 HIV vaccine design.