Abstract
Primary cilia are ubiquitous hair-like organelles, usually projecting from the cell surface. They are essential for the organogenesis and homeostasis of various physiological functions, and their dysfunction leads to a plethora of human diseases. However, there are few reports on the role of primary cilia in the immune system; therefore, we focused on their role in the thymus that nurtures immature lymphocytes to full-fledged T cells. We detected primary cilia on the thymic epithelial cell (TEC) expressing transforming growth factor β (TGF-β) receptor in the basal body, and established a line of an intraflagellar transport protein 88 (Ift88) knockout mice lacking primary cilia in TECs (Ift88-TEC null mutant) to clarify their precise role in thymic organogenesis and T-cell differentiation. The Ift88-TEC null mutant mice showed stunted cilia or lack of cilia in TECs. The intercellular contact between T cells and the “thymic synapse” of medullary TECs was slightly disorganized in Ift88-TEC null mutants. Notably, the CD4- and CD8-single positive thymocyte subsets increased significantly. The absence or disorganization of thymic cilia downregulated the TGF-β signaling cascade, increasing the number of single positive thymocytes. To our knowledge, this is the first study reporting the physiological role of primary cilia and Ift88 in regulating the differentiation of the thymus and T cells.
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25 April 2022
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Abbreviations
- TEC:
-
Thymic epithelial cell
- IS:
-
Immunological synapse
- TS:
-
Thymic synapse
- FTOC:
-
Fetal thymus organ culture
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Acknowledgements
We thank Dr. Georg A. Holländer (University of Oxford) for providing us with the Foxn1-Cre transgenic mice, Dr. Ken-ichi Hirano (Tokai University School of Medicine) for helping with the FTOC, Dr. Tetsuo Kondo and Wakaba Iha (University of Yamanashi) for preparing the paraffin tissue sections and hematoxylin and eosin staining, Dr. Sonoko Habu (Juntendo University School of Medicine) and Dr. Atsuhito Nakao (University of Yamanashi) for valuable discussion, Jun Hirata (University of Yamanashi) for helping with breeding the mice, and Kazuko Sawanobori (University of Yamanashi) for secretarial assistance. We also would like to thank Enago (www.enago.jp) for the English language review.
Funding
This study was supported by a JSPS KAKENHI (Grant Number 16K18584 and 20K16106 to O.K.; 17K08511 and 21K06753 to S.T.); the NIBB Collaborative Research Program (18–502) to O.K.; the Cooperative Study Program of Exploratory Research Center on Life and Living Systems (ExCELLS) (ExCELLS program No. 19–403 and 20–406) to O.K.; Takeda Science Foundation to O.K.; and a Research Grant for Young Scholars funded by Yamanashi Prefecture to O.K.
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OK and ST designed research; OK performed experiments; SN contributed to imaging tool; KH contributed to flow cytometric analysis; OK, SN, KH, and ST analyzed data; OK and ST wrote the manuscript.
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Kutomi, O., Nonaka, S., Hozumi, K. et al. Depletion of Ift88 in thymic epithelial cells affects thymic synapse and T-cell differentiation in aged mice. Anat Sci Int 97, 409–422 (2022). https://doi.org/10.1007/s12565-022-00663-w
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DOI: https://doi.org/10.1007/s12565-022-00663-w