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MicroRNAs of the miR-17∼92 family are critical regulators of TFH differentiation

Nature Immunology volume 14, pages 849–857 (2013)Cite this article

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Abstract

Follicular helper T cells (TFH cells) provide critical help to B cells during humoral immune responses. Here we report that mice with T cell–specific deletion of the miR-17∼92 family of microRNAs (miRNAs) had substantially compromised TFH differentiation, germinal-center formation and antibody responses and failed to control chronic viral infection. Conversely, mice with T cell–specific expression of a transgene encoding miR-17∼92 spontaneously accumulated TFH cells and developed a fatal immunopathology. Mechanistically, the miR-17∼92 family controlled the migration of CD4+ T cells into B cell follicles by regulating signaling intensity from the inducible costimulator ICOS and kinase PI(3)K by suppressing expression of the phosphatase PHLPP2. Our findings demonstrate an essential role for the miR-17∼92 family in TFH differentiation and establish PHLPP2 as an important mediator of their function in this process.

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Figure 1: The miR-17∼92 family regulates TFH differentiation during immunization with protein antigen.
Figure 2: The miR-17∼92 family regulates TFH differentiation during chronic viral infection.
Figure 3: Spontaneous accumulation of TFH cells in 17∼92tg/tg mice.
Figure 4: The effect of the miR-17∼92 family on antigen-specific CD4+ T cells during in vivo TFH differentiation.
Figure 5: The miR-17∼92 family specifically regulates TFH differentiation beyond the initial phase of T cell activation.
Figure 6: Deletion of one copy of Pten in CD4tKO mice partially restores TFH differentiation.
Figure 7: The miR-17∼92 family regulates TFH differentiation through the ICOS-PI(3)K pathway by suppressing the expression of Phlpp2.

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Acknowledgements

We thank Y. Zheng, C. Fine and B. Rezner for technical assistance; I. Tobias and A. Newton (University of California, San Diego) for the plasmid pcDNA3-HA-PHLPP2; C.H. Kim, E. Stone, S.M. Hedrick, K. Sauer and members of Xiao laboratory for discussion and critical reading of the manuscript. Supported by the Pew Charitable Trusts, the Cancer Research Institute, the Lupus Research Institute, the American Heart Association (11POST7430106 to J.R.T.), the US National Institutes of Health (R01AI019484 to M.B.A.O. and R01AI087634 to C.X.) and National Natural Science Foundation of China (81161120405 to H.Q.).

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Author notes

  1. Seung Goo Kang, Wen-Hsien Liu and Peiwen Lu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Seung Goo Kang, Wen-Hsien Liu, Hyun Yong Jin, Jovan Shepherd, Daniel Fremgen, Michael B A Oldstone, John R Teijaro & Changchun Xiao

  2. Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing, China

    Peiwen Lu & Hai Qi

  3. Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, USA

    Hyun Yong Jin

  4. Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, California, USA

    Hyung W Lim & Eric Verdin

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Contributions

C.X., S.G.K., W.-H.L. and J.R.T. conceived of and designed the project; P.L. did immunostaining and some PHLPP2-related experiments under the supervision of H.Q.; H.W.L. did in vitro TFH-differentiation experiments under the supervision of E.V.; S.G.K., W.-H.L., J.R.T., H.Y.J., J.S. and D.F. did all other experiments under the supervision of C.X., J.R.T. and M.B.A.O.; and S.G.K., W.-H.L., J.R.T. and C.X. wrote the manuscript.

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Correspondence to John R Teijaro or Changchun Xiao.

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Kang, S., Liu, WH., Lu, P. et al. MicroRNAs of the miR-17∼92 family are critical regulators of TFH differentiation. Nat Immunol 14, 849–857 (2013). https://doi.org/10.1038/ni.2648

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