| Autor: |
Naik, Abani Kanta, Dauphars, Danielle J., Corbett, Elizabeth, Simpson, Lunden, Schatz, David G., Krangel, Michael S. |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 93, p1-12, 12p |
| Abstrakt: |
Recombination activating gene (RAG) expression increases as thymocytes transition from the CD4−CD8− double-negative (DN) to the CD4+CD8+ double-positive (DP) stage, but the physiological importance and mechanism of transcriptional up-regulation are unknown. Here, we show that a DP-specific component of the recombination activating genes antisilencer (DPASE) provokes elevated RAG expression in DP thymocytes. Mouse DP thymocytes lacking the DPASE display RAG expression equivalent to that in DN thymocytes, but this supports only a partial Tcra repertoire due to inefficient secondary Vα-Jα rearrangement. These data indicate that RAG up-regulation is required for a replete Tcra repertoire and that RAG expression is fine-tuned during lymphocyte development to meet the requirements of distinct antigen receptor loci. We further show that transcription factor RORγt directs RAG up-regulation in DP thymocytes by binding to the DPASE and that RORγt influences the Tcra repertoire by binding to the Tcra enhancer. These data, together with prior work showing RORγt to control Tcra rearrangement by regulating DP thymocyte proliferation and survival, reveal RORγt to orchestrate multiple pathways that support formation of the Tcra repertoire. Editor's summary: Thymocytes show an increase in recombination activating gene (RAG) expression as they transition from CD4−CD8− double-negative (DN) to CD4+CD8+ double-positive (DP) cells. Naik et al. examined the mechanism and effects of increased RAG expression in thymocytes. The presence of a DP-specific component of the RAG antisilencer (DPASE) in the RAG locus was linked to higher RAG expression in DP thymocytes and was needed for efficient Vα-Jα rearrangement and a sufficient Tcra repertoire. The RORγt transcription factor binds to the DPASE to up-regulate RAG expression in DP thymocytes and binds to the Tcra enhancer as well, which affects the Tcra repertoire. These data deepen our understanding of mechanisms involved in DP thymocyte development and how this affects the Tcra repertoire. —Christiana N. Fogg [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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