Zap70 is essential for long-term survival of naive CD8 T cells
| Autor: | Manoj Saini, Lih-Yun Hsu, Arthur Weiss, Ina Schim van der Loeff, Benedict Seddon |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cell Survival
Transgene T cell Knockout Immunology Recent Thymic Emigrant Receptors Antigen T-Cell Biology CD8-Positive T-Lymphocytes Article Mice Antigen Lymphopenia Receptors medicine Immunology and Allergy Cytotoxic T cell Animals Lymphopoiesis Transgenes Gene Knock-In Techniques Antigens CD44 Cell Proliferation Mice Knockout Homeodomain Proteins Receptors Interleukin-7 ZAP-70 Protein-Tyrosine Kinase ZAP70 Interleukin-7 T-cell receptor T-Cell medicine.anatomical_structure Hyaluronan Receptors Doxycycline Cancer research Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950), vol 193, iss 6 Van Der Loeff, IS; Hsu, LY; Saini, M; Weiss, A; & Seddon, B. (2014). Zap70 is essential for long-term survival of naive CD8 T cells. Journal of Immunology, 193(6), 2873-2880. doi: 10.4049/jimmunol.1400858. UCSF: Retrieved from: http://www.escholarship.org/uc/item/6vd6673w |
| DOI: | 10.4049/jimmunol.1400858. |
| Popis: | Survival of naive T cells requires engagement of TCR with self-peptide major histocompatibility Ags. The signaling pathways required to transmit this survival signal are poorly understood. In this study, we asked whether the tyrosine kinase Zap70 is required to transmit survival signals in naive CD8 T cells. In the absence of Zap70 expression, thymic development is completely blocked. Using a tetracycline-inducible Zap70 transgene (TetZap70), thymic development of Zap70-deficient TCR transgenic F5 mice was restored. Feeding mice doxycycline to induce Zap70 expression resulted in repopulation of the peripheral naive compartment. Zap70 transgene expression was then ablated by withdrawal of doxycycline. Survival of Zap70-deficient naive CD8 T cells depended on host environment. In hosts with a replete T cell compartment, naive T cells died rapidly in the absence of Zap70 expression. In lymphopenic hosts, Zap70-deficient T cells survived far longer, in an IL-7–dependent manner, but failed to undergo lymphopenia-induced proliferation. Analyzing mixed bone marrow chimeras revealed that intact Zap70-dependent signaling was important for integration of recent thymic emigrants into the mature naive compartment. Finally, we asked whether adaptor function conferred by Zap70 tyrosines 315 and 319 was necessary for transmission of homeostatic TCR signals. This was done by analyzing F5 mice expressing mutant Zap70 in which these residues had been mutated to alanines (Zap70YYAA). Inducible Zap70 expression rescued thymic development in F5 TetZap70 Zap70YYAA mice. However, in the absence of wild-type Zap70 expression, the Zap70YYAA mutant failed to transmit either survival or proliferative homeostatic signals. |
| Databáze: | OpenAIRE |
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