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Memory CD4 T cells emerge from effector T-cell progenitors

Nature volume 452, pages 356–360 (2008)Cite this article

Abstract

A hallmark of adaptive immunity is the generation of memory T cells that confer long-lived, antigen-specific protection against repeat challenges by pathogens1,2,3,4,5. Understanding the mechanisms by which memory T cells arise is important for rational vaccination strategies and improved therapeutic interventions for chronic infections and autoimmune disorders. The large clonal expansion of CD8 T cells in response to some infections has made the development of CD8 T-cell memory more amenable to study, giving rise to a model of memory cell differentiation in which a fraction of fully competent effector T cells transition into long-lived memory T cells4,6,7. Delineation of CD4 T-cell memory development has proved more difficult as a result of limitations on tracking the smaller populations of CD4 effector T cells generated during a pathogenic challenge8,9,10, complicating efforts to determine whether CD4 memory T cells are direct descendants of effector T cells or whether they develop by alternative pathways3,4. Here, using two complementary cytokine reporter mouse models to identify interferon (IFN)-γ-positive effector T cells and track their fate, we show that the lineage relationship between effector and memory CD4 T cells resembles that for CD8 T cells responding to the same pathogen. We find that, in parallel with effector CD8 T cells, IFN-γ-positive effector CD4 T cells give rise to long-lived memory T cells capable of anamnestic responses to antigenic rechallenge.

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Figure 1: Tracking IFN-γ + effector CD4 and CD8 T cells in Ifng/Thy1.1 BAC-In Tg mice.
Figure 2: Progeny of IFN-γ competent effector CD4 and CD8 T cells populate the memory T-cell compartment.
Figure 3: Anamnestic responses conferred by memory CD4 T cells derived from IFN-γ + effector T cells.
Figure 4: Both IFN-γ+ and IFN-γ- effector CD4 T cells persist in vivo.

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Acknowledgements

We thank R. Hatton and C. Maynard, and other members of the Weaver laboratory, for comments and suggestions; T. Ryan and the UAB ES/Transgenic facility for assistance with blastocyst and embryo injections and the UAB Digestive Diseases Research Development Center (DDRDC) for generation of reporter mice; H. Shen for the provision of LM-OVA; C. Song, H. Turner and M. Blake for technical assistance; and N. LeLievre for editorial assistance. This study was supported in part by a Postdoctoral Fellowship and Career Transition Award from the National Multiple Sclerosis Society (L.E.H.) and by grants from the National Institutes of Health (C.T.W. and A.J.Z.).

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Author notes

  1. Laurie E. Harrington

    Present address: Present address: Department of Cell Biology, University of Alabama at Birmingham, 845 19th Street South, Birmingham, Alabama 35294, USA.,

Authors and Affiliations

  1. Department of Pathology, and,

    Laurie E. Harrington, Karen M. Janowski, James R. Oliver & Casey T. Weaver

  2. Department of Microbiology, University of Alabama at Birmingham, 845 19th Street South, Birmingham, Alabama 35294, USA,

    Allan J. Zajac

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Correspondence to Casey T. Weaver.

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Harrington, L., Janowski, K., Oliver, J. et al. Memory CD4 T cells emerge from effector T-cell progenitors. Nature 452, 356–360 (2008). https://doi.org/10.1038/nature06672

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