Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development

Corey N. Miller, Irina Proekt, Jakob von Moltke, Kristen L. Wells, Aparna R. Rajpurkar, Haiguang Wang, Kristin Rattay, Imran S. Khan, Todd C. Metzger, Joshua L. Pollack, Adam C. Fries, Wint W. Lwin, Eric J. Wigton, Audrey V. Parent, Bruno Kyewski, David J. Erle, Kristin A. Hogquist, Lars M. Steinmetz, Richard M. Locksley, Mark S. Anderson

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.

Original languageEnglish (US)
Pages (from-to)627-631
Number of pages5
JournalNature
Volume559
Issue number7715
DOIs
StatePublished - Jul 26 2018

Bibliographical note

Funding Information:
Acknowledgements We thank A. Chan, M. Waterfield, L. Velten and the Anderson, Locksley and Steinmetz laboratories for helpful discussions; K. Wu, Y. Wang and E. Li for experimental support. Tetramers were from the NIH Tetramer Core Facility. Pou2f3−/− mice were from the DTCC-KOMP2 Consortium from The Canadian Mouse Mutant Repository. Biostatistics support was provided by the UCSF Functional Genomics Core. This work was supported by NIH grant R01 AI097457 (C.N.M., I.P., I.S.K., T.C.M. and M.S.A.); Larry Hillblom Foundation 2017-D-012-FEL (I.P.); NIH Medical Scientist Training Program grant T32 GM007618 to UCSF (I.S.K.); NSF GRFP DGE 1656518 (K.L.W.); NSF GRFP DGE 1656518 (A.R.R.); NIH grant R37 AI039560 (H.W. and K.A.H.); Damon Runyon Cancer Research Foundation DRG-2162-13 (J.v.M.); Howard Hughes Medical Institute (J.v.M. and R.M.L.); Sandler Asthma Basic Research Center (A.C.F., J.v.M. and R.M.L.); German Cancer Research Center (K.R.); European Research Council grant ERC-2012-AdG (B.K.); NIH grant U01 DK107383 (A.V.P. and M.S.A.); NIH grant P01 HG00020527 (L.M.S.); NIH grant R01 AI026918 (R.M.L.); NIH Diabetes Research Center grant P30 DK063720 (A.C.F., M.S.A. and Single Cell Analysis Center); NIH Shared Instrument Grant 1S10OD021822-01 (Single Cell Analysis Center).

Publisher Copyright:
© 2018, Macmillan Publishers Ltd., part of Springer Nature.

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