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Antigen-induced tolerance by intrathymic modulation of self-recognizing inhibitory receptors

Nature Immunology volume 5, pages 590–596 (2004)Cite this article

A Retraction to this article was published on 01 August 2006

Abstract

CD1d-restricted invariant natural killer T cell (iNKT cells) have a limited T cell receptor (TCR) repertoire and share characteristics common to T cells and natural killer cells. While intrathymic selection facilitates the production of T cells carrying self major histocompatibility complex–restricted TCRs, natural killer cells carry an appropriate repertoire of self major histocompatibility complex–recognizing receptors to avoid self-reactivity. Here we show that chronic exposure to specific glycolipid antigen resulted in iNKT cell disappearance and thymus-dependent repopulation of iNKT cells with increased expression of inhibitory Ly-49 molecules that resulted in impaired responsiveness. Thymic selection of peripheral Ly-49-expressing iNKT cell repertoire inhibited cytokine production and other functions in vivo. These observations emphasize the acquisition of self-recognizing inhibitory receptors on NKT cells as a previously unknown mechanism of thymic tolerance after chronic antigen exposure.

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Figure 1: Chronic α-GalCer ligand exposure depletes the periphery of iNKT cells.
Figure 2: Chronic α-GalCer ligand exposure alters NKR expression on thymic iNKT cells.
Figure 3: Delayed reconstitution of the periphery with iNKT cells after chronic exposure to specific glycolipid antigen.
Figure 4: The thymus is essential for reconstitution of NK1.1dim Ly-49 expressing iNKT cells in the periphery.
Figure 5: Cytokine production is not required for reconstitution of NK1.1lo Ly-49-expressing iNKT cells in the periphery.
Figure 6: Impaired cytokine production from iNKT cells in chronic antigen–exposed mice by MHC class I recognition.
Figure 7: Loss of iNKT cell self-responsiveness in chronic antigen–exposed mice.
Figure 8: Altered NKR expression on iNKT cell repertoire correlates with disease.

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Acknowledgements

We thank M. Kronenberg and K. Takeda for discussions; R. Cameron and the staff of the Peter MacCallum Cancer Centre for their maintenance and care of the mice in this project; and A. Uldrich and D. Pellicci for their technical assistance. Supported by Cancer Research Institute (Y.H.), Cancer Council of Victoria (N.Y.C.) and National Health and Medical Research Council of Australia (M.J.S. and D.I.G.).

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Authors and Affiliations

  1. Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, 3002, Victoria, Australia

    Yoshihiro Hayakawa & Mark J Smyth

  2. Department of Microbiology and Immunology, University of Melbourne, Parkville, 3010, Victoria, Australia

    Stuart P Berzins, Nadine Y Crowe & Dale I Godfrey

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  1. Yoshihiro Hayakawa
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Correspondence to Yoshihiro Hayakawa.

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Hayakawa, Y., Berzins, S., Crowe, N. et al. Antigen-induced tolerance by intrathymic modulation of self-recognizing inhibitory receptors. Nat Immunol 5, 590–596 (2004). https://doi.org/10.1038/ni1069

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