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The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets

Nature Immunology volume 12, pages 1221–1229 (2011)Cite this article

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Abstract

During infection, naive CD8+ T cells differentiate into effector cells, which are armed to eliminate pathogens, and memory cells, which are poised to protect against reinfection. The transcriptional program that regulates terminal differentiation into short-lived effector-memory versus long-lived memory cells is not clearly defined. Through the use of mice expressing reporters for the DNA-binding inhibitors Id2 and Id3, we identified Id3hi precursors of long-lived memory cells before the peak of T cell population expansion or upregulation of cell-surface receptors that indicate memory potential. Deficiency in Id2 or Id3 resulted in loss of distinct CD8+ effector and memory populations, which demonstrated unique roles for these inhibitors of E-protein transcription factors. Furthermore, cytokines altered the expression of Id2 and Id3 differently, which provides insight into how external cues influence gene expression.

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Figure 1: Expression of Id2-YFP and Id3-GFP reporters in CD8+ T cells during infection identifies distinct effector populations.
Figure 2: Expression of Id2-YFP and Id3-GFP during infection correlates with effector and memory precursor subsets.
Figure 3: The Id3-GFPhi effector CD8+ T cell population includes long-lived memory precursor cells before expression of KLRG-1 or CD127.
Figure 4: Early Id3 expression correlates with memory potential.
Figure 5: Id3 deficiency results in the defective formation of long-lived memory CD8+ T cells.
Figure 6: Id2-deficient CD8+ T cells upregulate Id3 and do not generate short-lived effector-memory cells.
Figure 7: Id3-GFP expression and Id2-YFP expression are inversely coregulated by cytokines.

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Acknowledgements

We thank G. Barton, J. Hamerman, S. Turley, A. Fletcher, M. Rubinstein and members of the Goldrath laboratory for advice and critical review of the manuscript; and L. Shaw for help with figure design. Supported by the Cancer Research Institute, Pew Charitable Trust, the US National Institutes of Health (AI067545 and AI072117 to A.W.G.; and AI073587 to S.S.W.), University of California San Diego (Cellular and Molecular Genetics Training Grant to C.Y.Y.) and the R.E. Bob Smith Education Fund (H.S.L.).

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Authors and Affiliations

  1. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA

    Cliff Y Yang, J Adam Best, Jamie Knell, Edward Yang, Alison D Sheridan, Adam K Jesionek, Richard R Rivera, Kristin Camfield Lind, Louise M D'Cruz, Cornelis Murre & Ananda W Goldrath

  2. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Haiyan S Li & Stephanie S Watowich

  3. The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA

    Stephanie S Watowich

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Contributions

C.Y.Y. designed and completed the majority of experiments, analyzed and interpreted data, and wrote the manuscript; A.D.S. and R.R.R. generated the reporter mouse lines; J.A.B., J.K., E.Y. and K.C.L. did experiments and discussed and interpreted results; A.K.J. provided technical assistance; H.S.L. and S.S.W. discussed results and provided advice; L.M.D. and C.M. discussed and interpreted results and wrote the manuscript; and A.W.G. directed the study, analyzed and interpreted results, and wrote the manuscript.

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Correspondence to Ananda W Goldrath.

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Yang, C., Best, J., Knell, J. et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol 12, 1221–1229 (2011). https://doi.org/10.1038/ni.2158

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