Quantitative TCR:pMHC Dissociation Rate Assessment by NTAmers Reveals Antimelanoma T Cell Repertoires Enriched for High Functional Competence
| Autor: | Daniel E. Speiser, Petra Baumgaertner, Mathilde Allard, Nathalie Rufer, Philippe O. Gannon, Sébastien Wieckowski, Michael Hebeisen |
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| Rok vydání: | 2014 |
| Předmět: |
Cytotoxicity
Immunologic Melanoma/immunology Skin Neoplasms Skin Neoplasms/therapy Receptors Antigen T-Cell alpha-beta Antigens Neoplasm/chemistry CD8-Positive T-Lymphocytes Peptides/chemistry CD8-Positive T-Lymphocytes/cytology HLA-A Antigens/chemistry Melanoma/pathology Immunology and Allergy Cytotoxic T cell Prospective Studies Neoplasm Metastasis Melanoma Antigens Neoplasm/immunology HLA-A Antigens/immunology Cancer Vaccines/administration & dosage Cell Differentiation medicine.anatomical_structure Receptors Antigen T-Cell alpha-beta/immunology Skin Neoplasms/chemistry Peptides/immunology Protein Binding Skin Neoplasms/immunology T cell Immunology chemical and pharmacologic phenomena Biology CD8-Positive T-Lymphocytes/immunology Major histocompatibility complex Cancer Vaccines Skin Neoplasms/pathology Antigen Antigens Neoplasm Cancer Vaccines/immunology Melanoma/chemistry medicine Organometallic Compounds Humans Avidity Receptors Antigen T-Cell alpha-beta/chemistry Cancer Vaccines/chemistry Neoplasm Staging HLA-A Antigens Organometallic Compounds/chemistry T-cell receptor Clone Cells Melanoma/therapy Kinetics T cell differentiation biology.protein Immunization Peptides CD8 |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 195(1) |
| ISSN: | 1550-6606 |
| Popis: | Experimental models demonstrated that therapeutic induction of CD8 T cell responses may offer protection against tumors or infectious diseases providing that T cells have sufficiently high TCR/CD8:pMHC avidity for efficient Ag recognition and consequently strong immune functions. However, comprehensive characterization of TCR/CD8:pMHC avidity in clinically relevant situations has remained elusive. In this study, using the novel NTA-His tag–containing multimer technology, we quantified the TCR:pMHC dissociation rates (koff) of tumor-specific vaccine-induced CD8 T cell clones (n = 139) derived from seven melanoma patients vaccinated with IFA, CpG, and the native/EAA or analog/ELA Melan-AMART-126–35 peptide, binding with low or high affinity to MHC, respectively. We observed substantial correlations between koff and Ca2+ mobilization (p = 0.016) and target cell recognition (p < 0.0001), with the latter independently of the T cell differentiation state. Our strategy was successful in demonstrating that the type of peptide impacted on TCR/CD8:pMHC avidity, as tumor-reactive T cell clones derived from patients vaccinated with the low-affinity (native) peptide expressed slower koff rates than those derived from patients vaccinated with the high-affinity (analog) peptide (p < 0.0001). Furthermore, we observed that the low-affinity peptide promoted the selective differentiation of tumor-specific T cells bearing TCRs with high TCR/CD8:pMHC avidity (p < 0.0001). Altogether, TCR:pMHC interaction kinetics correlated strongly with T cell functions. Our study demonstrates the feasibility and usefulness of TCR/CD8:pMHC avidity assessment by NTA-His tag–containing multimers of naturally occurring polyclonal T cell responses, which represents a strong asset for the development of immunotherapy. |
| Databáze: | OpenAIRE |
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