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Insm1: orchestrating cellular mimicry in the thymus medulla

Cellular & Molecular Immunology volume 21, pages 416–418 (2024)Cite this article

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The thymus is the primary production site for a functional and self-tolerant T-cell repertoire. The establishment of immune tolerance is mediated by the generation and presentation of tissue-restricted self-antigens (TRAs) by medullary thymic epithelial cells (mTECs), which screen T-cell receptors for self-reactivity to eliminate autoreactive T cells. Recent studies have extended our understanding of mTEC heterogeneity by examining the mechanisms by which mTECs mimic the peripheral self [1]. Several studies have shown that mTECs use lineage-defining transcription factors normally expressed extrathymically to generate intrathymic cellular mimics of diverse peripheral cell identities [2,3,4]. These novel subsets of unconventional mTECs were collectively termed “mimetic mTECs” [3]. These mTECs mimic the transcriptional profile and morphology of well-defined, highly specialized cell types, such as endocrine cells, microfold cells and tuft cells, throughout the body, but importantly, they still retain an mTEC identity rather than being converted to a bona fide peripheral cell type [5]. Functionally, thymic mimetic subsets have nonredundant roles in thymus function, for example, in the induction of antigen-specific tolerance and the regulation of thymic involution [2, 3].

A recent focus has been the analysis of a specific mimetic mTEC subset that mimics epithelial neuroendocrine cells initially named endoTECs by Givony et al. [2]. Insulinoma-associated protein 1 (Insm1) was identified as a lineage-defining master regulator of these cells. Most recently, Tao et al. [4] investigated the importance of Insm1 in mTEC mimetic development, confirming its role as a lineage-defining transcription factor for endoTECs, which they termed neuroendocrine mimetic cells. Furthermore, they identified an essential role for Insm1 as a regulator of Aire+ mTEC development and self-antigen expression.

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References

  1. James KD, Cosway EJ, Parnell SM, White AJ, Jenkinson WE, Anderson G. Assembling the thymus medulla: Development and function of epithelial cell heterogeneity. Bioessays. 2024;46:e2300165.

    Article  PubMed  Google Scholar 

  2. Givony T, Leshkowitz D, Del Castillo D, Nevo S, Kadouri N, Dassa B, et al. Thymic mimetic cells function beyond self-tolerance. Nature. 2023;622:164–72.

    Article  CAS  PubMed  Google Scholar 

  3. Michelson DA, Hase K, Kaisho T, Benoist C, Mathis D. Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells. Cell. 2022;185:2542–58.e18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tao W, Ye Z, Wei Y, Wang J, Yang W, Yu G, et al. Insm1 regulates mTEC development and immune tolerance. Cell Mol Immunol. 2023;20:1472–86.

    Article  CAS  PubMed  Google Scholar 

  5. Michelson DA, Zuo C, Verzi M, Benoist C, Mathis D. Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus. J Exp Med. 2023;220:e20230461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395–401.

    Article  CAS  PubMed  Google Scholar 

  7. Ragazzini R, Boeing S, Zanieri L, Green M, D’Agostino G, Bartolovic K, et al. Defining the identity and the niches of epithelial stem cells with highly pleiotropic multilineage potency in the human thymus. Dev Cell. 2023;58:2428–46.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kashima J, Hashimoto T, Yoshida A, Goto Y, Ushiku T, Ohe Y, et al. Insulinoma-associated-1 (INSM1) expression in thymic squamous cell carcinoma. Virchows Arch. 2022;481:893–901.

    Article  CAS  PubMed  Google Scholar 

  9. Cowan JE, Jenkinson WE, Anderson G. Thymus medulla fosters generation of natural Treg cells, invariant gammadelta T cells, and invariant NKT cells: what we learn from intrathymic migration. Eur J Immunol. 2015;45:652–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Farr AG, Rudensky A. Medullary thymic epithelium: a mosaic of epithelial “self”? J Exp Med. 1998;188:1–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Professor Avinash Bhandoola and Professor Graham Anderson for their critical comments. JEC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 222623/Z/21/Z). KDJ is a Post-Doctoral Fellow supported by an MRC Programme Grant (MR/T029765/1) awarded to Professor Graham Anderson.

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  1. UCL Institute of Immunity and Transplantation, The Pears Building, Rowland Hill Street, London, NW3 2PP, UK

    K. D. James & J. E. Cowan

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  1. K. D. James
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Correspondence to J. E. Cowan.

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James, K.D., Cowan, J.E. Insm1: orchestrating cellular mimicry in the thymus medulla. Cell Mol Immunol 21, 416–418 (2024). https://doi.org/10.1038/s41423-024-01151-z

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