Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection
| Autor: | Doron Merkler, Sarah Enouz, Dietmar Zehn, Lucie Carrié, Michael J. Bevan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Receptors
Antigen T-Cell/genetics/immunology T-Lymphocytes Autoimmunity ddc:616.07 Ligands Lymphocyte Activation Autoantigens Immune tolerance Interleukin 21 Mice 0302 clinical medicine Clonal Selection Antigen-Mediated/immunology Histocompatibility Antigens Class II/immunology Immunology and Allergy Cytotoxic T cell IL-2 receptor Clonal Selection Antigen-Mediated 0303 health sciences Peripheral tolerance 3. Good health medicine.anatomical_structure Infection Islets of Langerhans/immunology/pathology/virology Thymus Gland/immunology T cell Immunology Receptors Antigen T-Cell Mice Transgenic Thymus Gland Infection/immunology/virology Lymphocyte Activation/immunology Biology Infections Article 03 medical and health sciences T cells self-antigen stimulation Islets of Langerhans Autoantigens/immunology medicine Immune Tolerance Peptides/chemistry/immunology Animals 030304 developmental biology T-cell receptor Histocompatibility Antigens Class II T-Lymphocytes/immunology Peptides Immunologic Memory CD8 030215 immunology |
| Zdroj: | The Journal of experimental medicine Journal of Experimental Medicine Journal of Experimental Medicine, vol. 209, no. 10, pp. 1769-1779 The Journal of Experimental Medicine Journal of Experimental Medicine, Vol. 209, No 10 (2012) pp. 1769-79 |
| ISSN: | 0022-1007 |
| Popis: | Autoimmunity occurs because central and peripheral tolerance mechanisms fail to tolerize T cells with weak self-reactivity to tissue-restricted antigen. Central and peripheral tolerance prevent autoimmunity by deleting the most aggressive CD8+ T cells but they spare cells that react weakly to tissue-restricted antigen (TRA). To reveal the functional characteristics of these spared cells, we generated a transgenic mouse expressing the TCR of a TRA-specific T cell that had escaped negative selection. Interestingly, the isolated TCR matches the affinity/avidity threshold for negatively selecting T cells, and when developing transgenic cells are exposed to their TRA in the thymus, only a fraction of them are eliminated but significant numbers enter the periphery. In contrast to high avidity cells, low avidity T cells persist in the antigen-positive periphery with no signs of anergy, unresponsiveness, or prior activation. Upon activation during an infection they cause autoimmunity and form memory cells. Unexpectedly, peptide ligands that are weaker in stimulating the transgenic T cells than the thymic threshold ligand also induce profound activation in the periphery. Thus, the peripheral T cell activation threshold during an infection is below that of negative selection for TRA. These results demonstrate the existence of a level of self-reactivity to TRA to which the thymus confers no protection and illustrate that organ damage can occur without genetic predisposition to autoimmunity. |
| Databáze: | OpenAIRE |
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