An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a
Open accessAbstract
Thymic positive selection is based on the interactions of T cell antigen receptors (TCRs) with self peptide-major histocompatibility complex (MHC) ligands, but the identity of selecting peptides for MHC class II-restricted TCRs and the functional consequences of this peptide specificity are not clear. Here we identify several endogenous self peptides that positively selected the MHC class II-restricted 5C.C7 TCR. The most potent of these also enhanced mature T cell activation, which supports the hypothesis that one function of positive selection is to produce T cells that can use particular self peptide-MHC complexes for activation and/or homeostasis. We also show that inhibiting the microRNA miR-181a resulted in maturation of T cells that overtly reacted toward these erstwhile positively selecting peptides. Therefore, miR-181a helps to guarantee the clonal deletion of particular moderate-affinity clones by modulating the TCR signaling threshold of thymocytes.
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Endogenous retroviral antigens do not cause complete immunological tolerance and both T and B cell responses are frequently detected in both mice and humans.
“It is also clear, however, that endogenous retroviral antigens do not cause complete immunological tolerance and both T and B cell responses are frequently detected in both mice and humans 33,34,36–41.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [33]
The Results (Self peptides that positively select the 5C.C7 TCR; page unavailable) identify GP peptide as partly derived from endogenous retroviral sequences. The Results (Central tolerance requires miR-181a; page unavailable) report a few GP-reactive T cells in control mouse thymic cultures and more after miR-181a inhibition, supporting incomplete T-cell tolerance in this model. The paper does not establish that T- and B-cell responses to endogenous retroviral antigens are frequently detected in both mice and humans. (LLM, conf=0.84)
Experimental — accuracy not yet measuredWhen the mechanisms that regulate TCR signaling threshold of thymocytes fail, the same ERV-encoded self-antigen induced an autoimmune response.
“However, when the mechanisms that regulate TCR signaling threshold of thymocytes fail, the same ERV-encoded self-antigen induced an autoimmune response 33.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [33]
Mouse studies have revealed that ERV-encoded self-antigens can, in certain cases, mediate positive selection of developing thymocytes with specific T cell receptor (TCR) reactivity, and promote their peripheral response to cognate antigen.
“Mouse studies have revealed that ERV-encoded self-antigens can, in certain cases, mediate positive selection of developing thymocytes with specific T cell receptor (TCR) reactivity, and promote their peripheral response to cognate antigen 33,34.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [33]
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Lo, W.-L., Felix, N. J., Walters, J. J., Rohrs, H., Gross, M. L., & Allen, P. M. (2009) · Nature Immunology · doi:10.1038/ni.1796 · Cited by 105 · see citing works
Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis
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“However, when the mechanisms that regulate TCR signaling threshold of thymocytes fail, the same ERV-encoded self-antigen induced an autoimmune response [33].”
BackgroundYoung, G. R., Ploquin, M. J.-Y., Eksmond, U., Wadwa, M., Stoye, J. P., & Kassiotis, G. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002709 · Cited by 56 · see citing works
- Authors
- Ebert, P. J. R., Jiang, S., Xie, J., Li, Q.-J., & Davis, M. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Duke Medical Center (US)
- Corresponding author
- Li, Qi-Jing
- Davis, Mark M
- Venue
- Nature Immunology
- Published
- 2009-10-04
- Volume
- 10
- Issue
- 11
- Pages
- 1162-1169
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3762483
- OpenAlex
- W2103780522
- Cited by
- 251
- References
- 54
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 11 · 2020: 13 · 2019: 12 · 2018: 19 · 2017: 12 · 2016: 11 · 2015: 18 · 2014: 30 · 2013: 37 · 2012: 25
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Allergy and Infectious Diseases (R01AI022511, R01AI073724, R37AI022511)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- thymic positive selection, autoantigens, miR-181a, microRNA, T cell activation, T cell homeostasis, clonal deletion, thymocytes
- MeSH terms
- Animals, Histocompatibility Antigens Class II, Cells, Cultured, Gene Expression Regulation, Lymphocyte Activation, Peptides, Receptors, Antigen, T-Cell, T-Lymphocytes, Thymus Gland, Clonal Deletion, Mice, Knockout, MicroRNAs, Mice
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