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Peptide-based Identification of Functional Motifs and their Binding Partners
Published on: June 30, 2013
Molecular requirements for T cell recognition of N-myristoylated peptides derived from the simian immunodeficiency
Daisuke Morita1, Yukie Yamamoto, Juri Suzuki
1Laboratory of Cell Regulation, Kyoto University, Kyoto, Japan.
Abstract:
We have recently isolated a rhesus macaque cytotoxic T cell line, 2N5.1, that specifically recognizes an N-myristoylated 5-mer peptide (C(14)-Gly-Gly-Ala-Ile-Ser [C14nef5]) derived from the simian immunodeficiency virus (SIV) Nef protein. Such C14nef5-specific T cells expand in the circulation of SIV-infected monkeys, underscoring the capacity of T cells to recognize viral lipopeptides; however, the molecular basis for the lipopeptide antigen presentation remains to be elucidated. Here, functional studies indicated that the putative antigen-presenting molecule for 2N5.1 was likely to have two separate antigen-binding sites, one for interaction with a C(14)-saturated acyl chain and the other for anchorage of the C-terminal serine residue. Mutants with alanine substitutions for the second glycine residue and the fourth isoleucine residue were not recognized by 2N5.1 but interfered with the presentation of C14nef5 to 2N5.1, indicating that these structural analogues retained the ability to interact with the antigen-presenting molecules. In contrast to the highly specific recognition of C14nef5 by 2N5.1, an additional cytotoxic T cell line, SN45, established independently from a C14nef5-stimulated T cell culture, showed superb reactivity to both C14nef5 and an N-myristoylated Nef 4-mer peptide, and therefore, the C-terminal serine residue was dispensable for the recognition of lipopeptides by the SN45 T cells. Furthermore, the mutants with alanine substitutions were indeed recognized by the SN45 T cells. Given that N-myristoylation of the Nef protein occurs in the conserved motifs and is critical for viral pathogenesis, these observations predict that the lipopeptide-specific T cell response is difficult for viruses to avoid by simply introducing amino acid mutations.
Insights
Cytotoxic T cells recognize simian immunodeficiency virus (SIV) lipopeptides, but the presentation mechanism is unclear. This study reveals distinct antigen-presenting molecule interactions for different T cell lines, suggesting viral lipopeptide evasion is challenging.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Cytotoxic T cells play a crucial role in antiviral immunity by recognizing viral antigens.
- Simian immunodeficiency virus (SIV) infection in rhesus macaques provides a model for studying T cell responses to viral proteins like Nef.
- N-myristoylation of viral proteins is a post-translational modification critical for viral pathogenesis and immune evasion.
Purpose of the Study:
- To elucidate the molecular basis of antigen presentation for N-myristoylated SIV peptides to cytotoxic T cells.
- To characterize the antigen recognition specificity of different cytotoxic T cell lines against SIV lipopeptides.
- To understand the implications of lipopeptide antigen presentation for viral immune evasion strategies.
Main Methods:
- Isolation and functional characterization of rhesus macaque cytotoxic T cell lines (2N5.1 and SN45).
- Use of N-myristoylated SIV Nef-derived peptides (C14nef5) and their alanine-substituted mutants.
- Functional assays to assess T cell recognition and antigen presentation by putative antigen-presenting molecules.
Main Results:
- The cytotoxic T cell line 2N5.1 specifically recognizes C14nef5, requiring both the acyl chain and C-terminal serine for presentation.
- A distinct T cell line, SN45, recognizes both C14nef5 and a shorter lipopeptide, indicating dispensability of the C-terminal serine.
- Alanine substitution mutants, while recognized by SN45, were not recognized by 2N5.1, suggesting distinct binding interactions.
- These findings highlight the complexity of lipopeptide antigen presentation and T cell recognition.
Conclusions:
- The molecular basis for lipopeptide antigen presentation involves distinct binding sites for acyl chains and peptide residues.
- Different T cell lines exhibit varying specificities for lipopeptide antigens, influencing recognition.
- Viral strategies to evade T cell responses by altering N-myristoylated proteins may be limited due to the conserved nature of these modifications and presentation mechanisms.
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