An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells

Lo, Wan-Lin; Felix, Nathan J; Walters, James J; Rohrs, Henry; Gross, Michael L; Allen, Paul M

doi:10.1038/ni.1796

Cited by 105T-cell and B-cell ImmunologyImmunotherapy and Immune Responsesvaccines and immunoinformatics approaches

An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells

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Lo, Wan-Lin, Felix, Nathan J, Walters, James J, Rohrs, Henry, Gross, Michael L, Allen, Paul M·2009·Nature Immunology

DOI 10.1038/ni.1796PMC PMC2764840

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Abstract

Although CD4(+) and CD8(+) T cells differ in the strength of their positively selecting signal, endogenous positively selecting ligands have been identified only for major histocompatibility complex (MHC) class I-restricted T cell antigen receptors (TCRs). Here we screened for ligands able to positively select MHC class II-restricted TCRs using thymocytes from four I-E(k)-restricted TCR-transgenic mice and a large panel of self peptides. One peptide, gp250, induced positive selection of AND CD4(+) T cells, had no homology with the AND TCR agonist ligand and was recognized with a high degree of specificity. The gp250 peptide acted as a coagonist to initiate the activation and enhance the survival of peripheral AND CD4(+) T cells. Thus, positively selecting ligands are critical in thymocyte development and in the activation and maintenance of peripheral T cells.

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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 [34]
The Results sections on positive selection and peripheral co-agonism report that gp250 selects AND thymocytes and enhances peripheral AND T-cell proliferation in the presence of cognate antigen. But the Results identify gp250 as a peptide from a sortilin-related endocytic receptor, not an ERV-encoded antigen. The Discussion mentions a different positively selecting peptide, gag-pol, from another study; it does not establish the claimed peripheral effect for that peptide. (LLM, conf=0.88)
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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 [34]
The Results section ('A peptide that positively selects the AND TCR') identifies gp250 as a self peptide derived from a sortilin-related receptor, not an endogenous retroviral antigen. The provided passages and searches for retroviral antigens, tolerance, and T- and B-cell responses do not address the claimed responses in mice and humans. (LLM, conf=0.76)
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An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a
Ebert, P. J. R., Jiang, S., Xie, J., Li, Q.-J., & Davis, M. M. (2009) · Nature Immunology · doi:10.1038/ni.1797 · Cited by 251 · see citing works
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MHC class I - Peptide binding and complex stability
Follin, E. (2014) · Lund University Publications (Lund University)

Authors: Lo, W.-L., Felix, N. J., Walters, J. J., Rohrs, H., Gross, M. L., & Allen, P. M.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Allen, Paul M
ORCID: Lo, Wan-Lin
Rohrs, Henry
Gross, Michael L
Allen, Paul M
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2009-10-04
Volume: 10
Issue: 11
Pages: 1155-1161
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/ni.1796
PMC: PMC2764840
OpenAlex: W174304716
Cited by: 105
References: 51
Citations by year: 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 14 · 2013: 12 · 2012: 12
FWCI: 5.46
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5p41rr000954-34)
National Institute of General Medical Sciences (P41GM103422)
National Institute of Allergy and Infectious Diseases (AI-24157, R01AI024157, R37AI024157)
National Center for Research Resources (P41-RR000954, 2P41 RR 000954)
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: positive selection, CD4+ T cells, T cell development, T cell activation, T cell survival, T cell homeostasis, self-peptides
MeSH terms: CD69 Antigens, Animals, Antigens, Differentiation, T-Lymphocyte, Histocompatibility Antigens Class II, Cell Line, Ligands, Lymphocyte Activation, Mice, Transgenic, Peptides, Protein Binding, Receptors, Antigen, T-Cell, Thymus Gland, CD4-Positive T-Lymphocytes, Antigens, CD, Amino Acid Substitution, Lectins, C-Type, Cell Proliferation, Mice

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An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells

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