LCK–co-receptor association ensures T cell lineage fidelity and maximizes epitope-specific TCR diversity
The interaction between the CD4/CD8 co-receptors and LCK (an Src family tyrosine kinase) is thought to augment T cell activation upon recognition of peptide-loaded major histocompatibility complexes (pMHCs). How this interaction influences antigen-specific T cell development is unclear however, as is its impact on naïve and immune antigen-specific T cell repertoires. In mice expressing mutated endogenous LCK unable to bind co-receptors (LCK<sup>FREE</sup> mice), we show that influenza A virus (IAV)-derived pMHC-specific CD8 and CD4 T cell responses had a significantly narrowed T cell receptor (TCR) repertoire, favoring high-affinity TCRs. This narrowing was established during T cell development and was exacerbated after viral infection. The dissociation of LCK from co-receptors also resulted in the redirection of CD4-fated T cells to the CD8 lineage, with expanded pMHCII-specific cytotoxic CD8 T cells observed after IAV infection. Thus, LCK-co-receptor association is critical for ensuring T cell lineage fidelity and maximizing antigen-specific T cell repertoire diversity.
Authors
- Stefan Schattgen (ORCID: https://orcid.org/0000-0002-6860-5079)
- Angela Nguyen (ORCID: https://orcid.org/0000-0003-1610-515X)
- Paul Glyndwr Thomas (ORCID: https://orcid.org/0000-0001-7955-0256)
- Daniel Thiele (ORCID: https://orcid.org/0000-0002-4469-8215)
- Jeanette Rientjes
- Priyanka Chaurasia (ORCID: https://orcid.org/0000-0002-3755-159X)
- Roland Ruscher (ORCID: https://orcid.org/0000-0002-8600-6985)
- Pirooz Zareie (ORCID: https://orcid.org/0000-0001-6000-2305)
- Claerwen M. Jones (ORCID: https://orcid.org/0000-0001-8594-9554)
- Hugh H. Reid (ORCID: https://orcid.org/0000-0001-6929-5001)
- Nguyen Thi Trang (ORCID: https://orcid.org/0000-0002-1284-5153)
- Nicole L. La Gruta (ORCID: https://orcid.org/0000-0001-5358-9363)
- Dene R. Littler (ORCID: https://orcid.org/0000-0001-5904-1905)
- Jamie Rossjohn (ORCID: https://orcid.org/0000-0002-2020-7522)
- Hui Xu (ORCID: https://orcid.org/0000-0002-0932-5026)
- Kim L. Good‐Jacobson (ORCID: https://orcid.org/0000-0003-1891-7274)
- Justin B. Zhang (ORCID: https://orcid.org/0000-0002-8658-6342)
- Mai T. Tran (ORCID: https://orcid.org/0000-0001-6470-8663)
- Zijian Huang
Institutions
- St. Jude Children's Research Hospital (US)
- Australian Institute of Tropical Health and Medicine (AU)
- Australian Regenerative Medicine Institute (AU)
- Monash University (AU)
- Cardiff University (GB)
- James Cook University (AU)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1126/sciimmunol.adp5016
- Citations
- 7
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 5.58