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Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation

Abstract

After infection, many factors coordinate the population expansion and differentiation of CD8+ effector and memory T cells. Using data of unparalleled breadth from the Immunological Genome Project, we analyzed the CD8+ T cell transcriptome throughout infection to establish gene-expression signatures and identify putative transcriptional regulators. Notably, we found that the expression of key gene signatures can be used to predict the memory-precursor potential of CD8+ effector cells. Long-lived memory CD8+ cells ultimately expressed a small subset of genes shared by natural killer T and γδ T cells. Although distinct inflammatory milieu and T cell precursor frequencies influenced the differentiation of CD8+ effector and memory populations, core transcriptional signatures were regulated similarly, whether polyclonal or transgenic, and whether responding to bacterial or viral model pathogens. Our results provide insights into the transcriptional regulation that influence memory formation and CD8+ T cell immunity.

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Figure 1: Gene-expression profiles associated with the activation and memory formation of CD8+ T cells.
Figure 2: Coregulated genes can be used to predict transcriptional regulation of T cell activation.
Figure 3: Regulation of core gene-expression modules by memory precursor cells.
Figure 4: Common gene-expression patterns of transgenic and endogenous CD8+ effector and memory T cells.
Figure 5: Regulation of genes associated with activation state is independent of infection.
Figure 6: Genes induced in CD8+ memory T cells correlate with gene expression by NKT cells and activated γδ T cells.

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Acknowledgements

We thank eBioscience, Affymetrix and Expression Analysis for support of the ImmGen Project. Supported by the US National Institutes of Health (AI072117 and AI067545 to A.W.G.; T32 AI060536 to J.A.B.; PN2 EY016586 to D.A.B. and M.L.D.; P30 CA016087 for cell sorting; and R24 AI072073 (National Institute of Allergy and Infectious Diseases) to the ImmGen Consortium), the Pew Scholars program (A.W.G.) and the Cancer Research Institute (A.W.G. and V.M.).

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J.A.B. did experiments, designed studies, analyzed data and wrote the manuscript; J.K. sorted cell subsets and analyzed data; A.D. analyzed data and edited the manuscript; D.A.B., V.M. and M.L.D. designed and did early infection experiments, analyzed data and contributed to writing the manuscript; E.Y. sorted cell subsets; and A.W.G. designed studies, analyzed data and wrote the manuscript.

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Correspondence to Ananda W Goldrath.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Tables 2–4 and Note (PDF 3722 kb)

Supplementary Table 1

Gene expression values for gene lists defined by clusters I-X. (XLSX 13917 kb)

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Best, J., Blair, D., Knell, J. et al. Transcriptional insights into the CD8+ T cell response to infection and memory T cell formation. Nat Immunol 14, 404–412 (2013). https://doi.org/10.1038/ni.2536

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