Memory CD4 T cells emerge from effector T-cell progenitors

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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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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