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

Abstract

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 CD4CD8αβ+ MHC II-recognizing population generated by lineage conversion from effector CD4+ T cells. CD4CD8αβ+ 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 CD4CD8αβ+ 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.

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Acknowledgements

We thank the NIH Tetramer Core Facility for providing tetramer reagents. We thank Dr. Regina Lin for assistance with qPCR experiments, Jose Sevilla for assistance with mouse husbandry and Dr. Marthony Robins for helpful comments on our paper. We thank Dr. Fan Wang for mice and expertize on Vps34 studies. Funding for this investigation was provided by a Duke University Center for AIDS Research (CFAR) Small Grant (Q.-J.L.), National Institutes of Health (NIH) Training Grants (2 T32 AI 052077–11 and 5 T32 AI 052077–09) (E.R.) and an American Association of Immunologists (AAI) Careers in Immunology Fellowship (Q.-J.L. and E.R.). This work was supported by Duke University Center for AIDS Research (CFAR) Small Grant (Q.-J.L.), National Institutes of Health (NIH) Training Grants (2 T32 AI 052077–11 and 5 T32 AI 052077–09) (E.R.), and American Association of Immunologists (AAI) Careers in Immunology Fellowship (Q.-J.L. and E.R.).

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E.R. designed research studies, performed experiments, acquired data, analyzed data and prepared the paper. M.Z. and Q.N. analyzed TCR repertoire data. S.L. performed murine experiments and prepared the heatmap figures. L.C. generated murine strains. B.Z. provided expertize on in vivo murine experiments and generated murine strains. J.G. generated and maintained murine strains. Y.Z. provided murine strains and expertize on murine experiments. Y.-W.H. provided expertize on Vps34/Atg7 murine studies and murine strains. P.Z. and Y.W. provided TCR sequencing equipment and administrative oversight. Q.-J.L. provided experimental guidance, provided experimental reagents/equipment, provided administrative oversight and revised the paper.

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Correspondence to Qi-Jing Li.

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Robins, E., Zheng, M., Ni, Q. et al. Conversion of effector CD4+ T cells to a CD8+ MHC II-recognizing lineage. Cell Mol Immunol 18, 150–161 (2021). https://doi.org/10.1038/s41423-019-0347-5

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