Negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen in the human thymus
| Autor: | Megan Sykes, Nichole M. Danzl, Chiara Borsotti, Maki Nakayama, Mohsen Khosravi Maharlooei, Grace Nauman, Hao Wei Li, Rachel Madley, Bart O. Roep, Estefania Chavez, Remi J. Creusot |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
Research paper T cell Immunology T-cell receptor T cell selection Autoimmunity Human leukocyte antigen Biology HLA Negative selection medicine.anatomical_structure Type 1 diabetes Antigen PD-1 medicine Immunology and Allergy Clone (B-cell biology) Antigen-presenting cell lcsh:RC581-607 Tolerance |
| Zdroj: | Journal of Translational Autoimmunity Journal of Translational Autoimmunity, Vol 3, Iss, Pp 100061-(2020) |
| ISSN: | 2589-9090 |
| Popis: | During T cell development in mice, thymic negative selection deletes cells with the potential to recognize and react to self-antigens. In human T cell-dependent autoimmune diseases such as Type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, T cells reactive to autoantigens are thought to escape negative selection, traffic to the periphery and attack self-tissues. However, physiological thymic negative selection of autoreactive human T cells has not been previously studied. We now describe a human T-cell receptor-transgenic humanized mouse model that permits the study of autoreactive T-cell development in a human thymus. Our studies demonstrate that thymocytes expressing the autoreactive Clone 5 TCR, which recognizes insulin B:9–23 presented by HLA-DQ8, are efficiently negatively selected at the double and single positive stage in human immune systems derived from HLA-DQ8+ HSCs. In the absence of hematopoietic expression of the HLA restriction element, negative selection of Clone 5 is less efficient and restricted to the single positive stage. To our knowledge, these data provide the first demonstration of negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen. Intrathymic antigen presenting cells are required to delete less mature thymocytes, while presentation by medullary thymic epithelial cells may be sufficient to delete more mature single positive cells. These observations set the stage for investigation of putative defects in negative selection in human autoimmune diseases. Highlights • In the presence of the HLA-restriction element on hematopoietic stem cells (HSCs) and thymus.•Thymocytes bearing insulin peptide-reactive TCRs express markers of thymic negative selection.•Insulin peptide-reactive T cells are efficiently negatively selected in the human thymus.•The few transgenic T cells that escape negative selection largely express endogenous TCRs. • HLA-restriction element on HSCs is required for efficient negative selection. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|