Cbl-b deficiency prevents functional but not phenotypic T cell anergy
| Autor: | Walter L. Eckalbar, Trang Nguyen, Lin Shen, Zhi-En Wang, Arthur Weiss, Andrew Schroeder |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Ubiquitin-Protein Ligases Transgene T cell Programmed Cell Death 1 Receptor Immunology Antigen presentation Mice Transgenic Autoimmunity Biology Lymphocyte Activation T-Lymphocytes Regulatory Article Mice Immune Tolerance medicine Animals Immunology and Allergy Proto-Oncogene Proteins c-cbl Receptor Adaptor Proteins Signal Transducing Clonal Anergy ZAP-70 Protein-Tyrosine Kinase Peripheral Tolerance ZAP70 T-cell receptor Peripheral tolerance Cell biology medicine.anatomical_structure Signal transduction Tolerance Signal Transduction |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20202477 |
| Popis: | T cell anergy is an important peripheral tolerance mechanism to prevent autoimmunity. Nguyen et al. find that T cell anergy develops in the periphery, not in the thymus, and depends upon Cbl-b but not Grail or PD-1. T cell anergy is an important peripheral tolerance mechanism. We studied how T cell anergy is established using an anergy model in which the Zap70 hypermorphic mutant W131A is coexpressed with the OTII TCR transgene (W131AOTII). Anergy was established in the periphery, not in the thymus. Contrary to enriched tolerance gene signatures and impaired TCR signaling in mature peripheral CD4 T cells, CD4SP thymocytes exhibited normal TCR signaling in W131AOTII mice. Importantly, the maintenance of T cell anergy in W131AOTII mice required antigen presentation via MHC-II. We investigated the functional importance of the inhibitory receptor PD-1 and the E3 ubiquitin ligases Cbl-b and Grail in this model. Deletion of each did not affect expression of phenotypic markers of anergic T cells or T reg numbers. However, deletion of Cbl-b, but not Grail or PD-1, in W131AOTII mice restored T cell responsiveness and signaling. Thus, Cbl-b plays an essential role in the establishment and/or maintenance of unresponsiveness in T cell anergy. Graphical Abstract |
| Databáze: | OpenAIRE |
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