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The development and fate of follicular helper T cells defined by an IL-21 reporter mouse

Nature Immunology volume 13, pages 491–498 (2012)Cite this article

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Abstract

Germinal centers require CD4+ follicular helper T cells (TFH cells), whose hallmark is expression of the transcriptional repressor Bcl-6, the chemokine receptor CXCR5 and interleukin 21 (IL-21). To track the development and fate of TFH cells, we generated an IL-21 reporter mouse by introducing sequence encoding green fluorescent protein (GFP) into the Il21 locus; these mice had expression of IL-21–GFP in CD4+CXCR5+PD-1+ TFH cells. IL-21–GFP+ TFH cells were multifunctional helper cells that coexpressed several cytokines, including interferon-γ (IFN-γ), IL-2 and IL-4. TFH cells proliferated and gave rise to transferrable memory cells with plasticity, which differentiated after recall into conventional effector helper T cells and TFH cells. Thus, we demonstrated that TFH cells were not terminally differentiated but instead retained the flexibility to be recruited into other helper T cell subsets and nonlymphoid tissues.

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Figure 1: Characterization of Il21GFP/+ mice.
Figure 2: Dichotomy in IL-21 expression among TFH cells.
Figure 3: Expression of transcription factors and cytokines in TFH cells.
Figure 4: Developmental relationship and proliferation status of IL-21–GFP− and IL-21–GFP+ TFH cells.
Figure 5: TFH cells form functional memory cells.
Figure 6: TFH cells express IFN-γ after influenza virus infection.

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Acknowledgements

We thank L. Corcoran (Walter and Eliza Hall Institute of Medical Research) for antibody to Bcl-6 and antibody to IRF4; and E. Cretney for preliminary experiments. Supported by the National Health and Medical Research Council of Australia (A.K., G.T.B., D.M.T. and S.L.N.), the German Academic Exchange Service (K.L.), the Sylvia and Charles Viertel Foundation (G.T.B.), the Howard Hughes Medical Institute (G.T.B.), Pfizer Australia Research (S.L.N.), the Australian Research Council (A.K. and S.L.N.), the Victorian State Government Operational Infrastructure Support and the National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme of the Australian Government.

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  1. David M Tarlinton and Stephen L Nutt: These authors contributed equally to this work.

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia

    Katja Lüthje, Axel Kallies, Yoko Shimohakamada, Gabrielle T Belz, Amanda Light, David M Tarlinton & Stephen L Nutt

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Contributions

K.L., A.K., Y.S., G.T.B., A.L., D.M.T. and S.L.N. designed and did experiments; and K.L., D.M.T. and S.L.N. wrote the paper.

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Correspondence to David M Tarlinton or Stephen L Nutt.

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Lüthje, K., Kallies, A., Shimohakamada, Y. et al. The development and fate of follicular helper T cells defined by an IL-21 reporter mouse. Nat Immunol 13, 491–498 (2012). https://doi.org/10.1038/ni.2261

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