Negative Selection by an Endogenous Retrovirus Promotes a Higher-Avidity CD4+ T Cell Response to Retroviral Infection

Young, George R.; Ploquin, Mickaël J.-Y.; Eksmond, Urszula; Wadwa, Munisch; Stoye, Jonathan P.; Kassiotis, George

doi:10.1371/journal.ppat.1002709

Cited by 56T-cell and B-cell ImmunologyHIV Research and Treatmentvaccines and immunoinformatics approaches

Negative Selection by an Endogenous Retrovirus Promotes a Higher-Avidity CD4+ T Cell Response to Retroviral Infection

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Young, George R., Ploquin, Mickaël J.-Y., Eksmond, Urszula, Wadwa, Munisch, Stoye, Jonathan P., Kassiotis, George·2012·PLoS Pathogens

DOI 10.1371/journal.ppat.1002709PMC PMC3349761

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Abstract

Effective T cell responses can decisively influence the outcome of retroviral infection. However, what constitutes protective T cell responses or determines the ability of the host to mount such responses is incompletely understood. Here we studied the requirements for development and induction of CD4+ T cells that were essential for immunity to Friend virus (FV) infection of mice, according to their TCR avidity for an FV-derived epitope. We showed that a self peptide, encoded by an endogenous retrovirus, negatively selected a significant fraction of polyclonal FV-specific CD4+ T cells and diminished the response to FV infection. Surprisingly, however, CD4+ T cell-mediated antiviral activity was fully preserved. Detailed repertoire analysis revealed that clones with low avidity for FV-derived peptides were more cross-reactive with self peptides and were consequently preferentially deleted. Negative selection of low-avidity FV-reactive CD4+ T cells was responsible for the dominance of high-avidity clones in the response to FV infection, suggesting that protection against the primary infecting virus was mediated exclusively by high-avidity CD4+ T cells. Thus, although negative selection reduced the size and cross-reactivity of the available FV-reactive naïve CD4+ T cell repertoire, it increased the overall avidity of the repertoire that responded to infection. These findings demonstrate that self proteins expressed by replication-defective endogenous retroviruses can heavily influence the formation of the TCR repertoire reactive with exogenous retroviruses and determine the avidity of the response to retroviral infection. Given the overabundance of endogenous retroviruses in the human genome, these findings also suggest that endogenous retroviral proteins, presented by products of highly polymorphic HLA alleles, may shape the human TCR repertoire that reacts with exogenous retroviruses or other infecting pathogens, leading to interindividual heterogeneity.

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Thymic selection by ERV-encoded self-antigens has also been shown to promote the avidity of the T cell response to exogenous antigens.
“Nevertheless, thymic selection by ERV-encoded self-antigens has also been shown to promote the avidity of the T cell response to exogenous antigens 35.”
From Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis (2013) · cites this paper as [35]

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Authors: Young, G. R., Ploquin, M. J.-Y., Eksmond, U., Wadwa, M., Stoye, J. P., & Kassiotis, G.
Affiliations: National Institute for Medical Research (GB)
Corresponding author: Kassiotis, George
ORCID: Young, George R.
Wadwa, Munisch
Stoye, Jonathan P.
Kassiotis, George
Venue: PLoS Pathogens
Publisher: Public Library of Science (PLoS)
Published: 2012-05-10
Volume: 8
Issue: 5
Pages: e1002709
ISSN: 1553-7366 (ISSN-L)
1553-7374
DOI: 10.1371/journal.ppat.1002709
PMC: PMC3349761
OpenAlex: W2048490428
Cited by: 56
References: 67
Citations by year: 2026: 2 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 8 · 2015: 3 · 2014: 6 · 2013: 2 · 2012: 4
FWCI: 2.10
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: PLoS Pathogens (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Figshare (submittedVersion, cc-by)
Funders: Medical Research Council (U117581330)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords: negative selection, endogenous retroviruses, CD4+ T cells, T cell receptor avidity, Friend virus, retroviral infection, T cell receptor repertoire, T cell tolerance, HLA polymorphism, antiviral immunity, T cell deletion
MeSH terms: Animals, Friend murine leukemia virus, Humans, Lymphocyte Activation, Mice, Inbred A, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, Retroviridae Infections, CD4-Positive T-Lymphocytes, Gene Products, env, Endogenous Retroviruses, Mice

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Negative Selection by an Endogenous Retrovirus Promotes a Higher-Avidity CD4+ T Cell Response to Retroviral Infection

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