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Strength of tonic T cell receptor signaling instructs T follicular helper cell–fate decisions

Nature Immunology volume 21, pages 1384–1396 (2020)Cite this article

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Abstract

T follicular helper (TFH) cells are critical in adaptive immune responses to pathogens and vaccines; however, what drives the initiation of their developmental program remains unclear. Studies suggest that a T cell antigen receptor (TCR)-dependent mechanism may be responsible for the earliest TFH cell–fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized that tonic signaling influences early TFH cell development. Here, two murine TCR-transgenic CD4+ T cells, LLO56 and LLO118, which recognize the same antigenic peptide presented on major histocompatibility complex molecules but experience disparate strengths of tonic signaling, revealed low tonic signaling promotes TFH cell differentiation. Polyclonal T cells paralleled these findings, with naive Nur77 expression distinguishing TFH cell potential. Two mouse lines were also generated to both increase and decrease tonic signaling strength, directly establishing an inverse relationship between tonic signaling strength and TFH cell development. Our findings elucidate a central role for tonic TCR signaling in early TFH cell-lineage decisions.

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Fig. 1: High- and low-tonic-signaling cells (LLO56 and LLO118, respectively) generate equivalent TH1 immune responses, but differ in their ability to produce a TFH population.
Fig. 2: LLO56 and LLO118 cells have distinct TFH effector qualities.
Fig. 3: Low-tonic-signaling cells (LLO118 cells) support long-lived, high-affinity antibody production, whereas high-tonic-signaling cells (LLO56 cells) do not.
Fig. 4: LLO56 TFH cell impairment is independent of IL-2 signaling and cannot be rescued by increasing TCR activation strength.
Fig. 5: Increasing basal TCR signaling in LLO118 cells inhibits TFH development.
Fig. 6: Nur77 expression distinguishes TFH outcome in the polyclonal repertoire.
Fig. 7: Restricting the self-pMHC repertoire decreases tonic signaling and enhances TFH development in polyclonal CD4+ T cells.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank D. Kreamalmeyer for mouse breeding and care, D. Brinja and E. Lantelme for assistance with sorting by flow cytometry, D. Oakley and M. Shih of the Washington University Center for Cellular Imaging for assistance with AxioScan use and image analysis, W. L. Lo for insights on the manuscript and M. White and the Genome Engineering and iPSC Center at Washington University for generation of the H2-DMaf/f mouse line. This work was supported by National Institutes of Health research grants AI138393 (to J.M.B.), AI130152-01A1 (to T.E.), AI139875 (to T.E.) and AI139540 (to P.M.A), the Leukemia and Lymphoma Society Scholar Award (to T.E.) and the Washington University Rheumatic Diseases Research Resource-Based Center, funded by NIH grant P30AR073752 (to P.M.A).

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  1. Ashley A. Viehmann Milam

    Present address: Department of Biology, St. Louis University, St. Louis, MO, USA

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  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Juliet M. Bartleson, Ashley A. Viehmann Milam, David L. Donermeyer, Stephen Horvath, Yu Xia, Takeshi Egawa & Paul M. Allen

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Contributions

J.M.B. designed and performed the experiments and wrote the manuscript. A.A.V.M., D.L.D., S.H., Y.X. and T.E. performed the experiments. P.M.A. designed the experiments and wrote the manuscript.

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Correspondence to Paul M. Allen.

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Bartleson, J.M., Viehmann Milam, A.A., Donermeyer, D.L. et al. Strength of tonic T cell receptor signaling instructs T follicular helper cell–fate decisions. Nat Immunol 21, 1384–1396 (2020). https://doi.org/10.1038/s41590-020-0781-7

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