title: Zap70 is essential for long-term survival of naive CD8 T cells.
abstract: 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 (Zap70(YYAA)). Inducible Zap70 expression rescued thymic development in F5 TetZap70 Zap70(YYAA) mice. However, in the absence of wild-type Zap70 expression, the Zap70(YYAA) mutant failed to transmit either survival or proliferative homeostatic signals.
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; and.
authors.forename: Ina
authors.initials: I
authors.lastname: Schim van der Loeff
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Lih-Yun
authors.initials: LY
authors.lastname: Hsu
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; and.
authors.forename: Manoj
authors.initials: M
authors.lastname: Saini
authors.affiliation: Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143.
authors.forename: Art
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Division of Immune Cell Biology, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; and benedict.seddon@ucl.ac.uk.
authors.forename: Benedict
authors.initials: B
authors.lastname: Seddon
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D018398:Homeodomain Proteins / Q000235:genetics; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D015851:Interleukin-7 / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000235:genetics; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology
chemical_list: C476399:Cd44 protein, mouse; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; C064658:RAG-1 protein; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D004318:Doxycycline
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