Strength of TCR signal from self-peptide modulates autoreactive thymocyte deletion and Foxp3+ regulatory T cell formation
| Autor: | Caton, Andrew J., Kropf, Elizabeth, Simons, Donald M., Aitken, Malinda, Weissler, Katherine A., Jordan, Martha S. |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Antigen Presentation
Mice Inbred BALB C Thymocytes Receptors Antigen T-Cell alpha-beta Interleukin-2 Receptor alpha Subunit Receptors Antigen T-Cell Clonal Deletion Gene Expression hemic and immune systems chemical and pharmacologic phenomena Autoimmunity Forkhead Transcription Factors Mice Transgenic Phosphoproteins Autoantigens T-Lymphocytes Regulatory Article Mice Phenotype Mutation Animals Peptides Adaptor Proteins Signal Transducing Signal Transduction |
| Popis: | Autoreactive CD4(+) CD8(-) (CD4SP) thymocytes can be subjected to deletion when they encounter self-peptide during their development, but they can also undergo selection to become CD4SPFoxp3(+) Treg cells. We have analyzed the relationship between these distinct developmental fates using mice in which signals transmitted by the TCR have been attenuated by mutation of a critical tyrosine residue of the adapter protein SLP-76. In mice containing polyclonal TCR repertoires, the mutation caused increased frequencies of CD4SPFoxp3(+) thymocytes. CD4SP thymocytes expressing TCR Vβ-chains that are subjected to deletion by endogenous retroviral superantigens were also present at increased frequencies, particularly among Foxp3(+) thymocytes. In transgenic mice in which CD4SP thymocytes expressing an autoreactive TCR undergo both deletion and Treg-cell formation in response to a defined self-peptide, SLP-76 mutation abrogated deletion of autoreactive CD4SP thymocytes. Notably, Foxp3(+) Treg-cell formation still occurred, albeit with a reduced efficiency, and the mutation was also associated with decreased Nur77 expression by the autoreactive CD4SP thymocytes. These studies provide evidence that the strength of the TCR signal can play a direct role in directing the extent of both thymocyte deletion and Treg-cell differentiation, and suggest that distinct TCR signaling thresholds and/or pathways can promote CD4SP thymocyte deletion versus Treg-cell formation. |
| Databáze: | OpenAIRE |
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