Modulation of Naive CD8 T Cell Response Features by Ligand Density, Affinity, and Continued Signaling via Internalized TCRs
| Autor: | Ashutosh Chaudhry, Satyajit Rath, Divya A. Verghese, Rupali Gund, Chitra Ebenezer, Renu Balyan, Anna George, Thyagarajan Krishnamurthy, Jasneet Kaur Khalsa, Vineeta Bal |
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| Rok vydání: | 2017 |
| Předmět: |
Antigens
Differentiation T-Lymphocyte 0301 basic medicine Low protein media_common.quotation_subject T cell Immunology Receptors Antigen T-Cell CD8-Positive T-Lymphocytes Biology Ligands Lymphocyte Activation Cell Line Mice 03 medical and health sciences 0302 clinical medicine Antigens CD medicine Animals Immunology and Allergy Cytotoxic T cell Lectins C-Type Internalization Receptor media_common T-cell receptor Dendritic Cells Cell cycle Cell biology Glucose 030104 developmental biology medicine.anatomical_structure Cell culture Interleukin-2 Peptides Signal Transduction 030215 immunology |
| Zdroj: | The Journal of Immunology. 198:1823-1837 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1600083 |
| Popis: | T cell response magnitudes increase with increasing antigenic dosage. However, it is unclear whether ligand density only modulates the proportions of responding ligand-specific T cells or also alters responses at the single cell level. Using brief (3 h) exposure of TCR-transgenic mouse CD8 T cells in vitro to varying densities of cognate peptide-MHC ligand followed by ligand-free culture in IL-2, we found that ligand density determined the frequencies of responding cells but not the expression levels of the early activation marker molecule, CD69. Cells with low glucose uptake capacity and low protein synthesis rates were less ligand-sensitive, implicating metabolic competence in the response heterogeneity of CD8 T cell populations. Although most responding cells proliferated, ligand density was associated with time of entry into proliferation and with the extent of cell surface TCR downmodulation. TCR internalization was associated, regardless of the ligand density, with rapidity of c-myc induction, loss of the cell cycle inhibitor p27kip1, metabolic reprogramming, and cell cycle entry. A low affinity peptide ligand behaved, regardless of ligand density, like a low density, high affinity ligand in all these parameters. Inhibition of signaling after ligand exposure selectively delayed proliferation in cells with internalized TCRs. Finally, internalized TCRs continued to signal and genetic modification of TCR internalization and trafficking altered the duration of signaling in a T cell hybridoma. Together, our findings indicate that heterogeneity among responding CD8 T cell populations in their ability to respond to TCR-mediated stimulation and internalize TCRs mediates detection of ligand density or affinity, contributing to graded response magnitudes. |
| Databáze: | OpenAIRE |
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