Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells
- King's College London, United Kingdom
- University of Birmingham, United Kingdom
Abstract
Tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. Yet, if and how the tissue environment shapes the antigen specificity of iNKT cells remains unknown. By analysing iNKT cells from lymphoid tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for cells from various tissues resulting in differential lipid-antigen recognition. Within peripheral tissues iNKT cell recent thymic emigrants exhibit a different TCR repertoire than mature cells, suggesting that the iNKT population is shaped after arrival to the periphery. Consistent with this, iNKT cells from different organs show distinct basal activation, proliferation and clonal expansion. Moreover, the iNKT cell TCR repertoire changes following immunisation and is shaped by age and environmental changes. Thus, post-thymic modification of the TCR-repertoire underpins the distinct antigen specificity for iNKT cells in peripheral tissues.
Data availability
The RNAseq data are available in the Gene Expression Omnibus (GEO) database with accession number GSE131420.
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Analysis of transcriptomic profile of iNKT cellsNCBI Gene Expression Omnibus, GSE131420.
Article and author information
Author details
Funding
Medical Research Council (MR/L008157/1)
- Patricia Barral
Marie Curie Intraeuropean Fellowship (H2020-MSCA-IF-2015-703639)
- Rebeca Jimeno
Medical Research Council (DKAA.RRAK18742)
- Graham Anderson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by the Francis Crick Institute's and the King's College London's Animal Welfare and Ethical Review Body and the United Kingdom Home Office.
Human subjects: Human tissues used in this study were collected with ethical approval from UK Research Ethics Committees administered through the Integrated Research Application System. All samples were collected with informed consent.
Copyright
© 2019, Jimeno et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tissue-specific shaping of the TCR repertoire and antigen specificity of iNKT cells
eLife 8:e51663.
https://doi.org/10.7554/eLife.51663
Further reading
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- Immunology and Inflammation
Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.
