Distinct roles for Syk and ZAP-70 during early thymocyte development.
The spleen tyrosine kinase (Syk) and zeta-associated protein of 70 kD (ZAP-70) tyrosine kinases are both expressed during early thymocyte development, but their unique thymic functions have remained obscure. No specific role for Syk during beta-selection has been established, and no role has been described for ZAP-70 before positive selection. We show that Syk and ZAP-70 provide thymocytes with unique and separable fitness advantages during early development. Syk-deficient, but not ZAP-70-deficient, thymocytes are specifically impaired in initial pre-TCR signaling at the double-negative (DN) 3 beta selection stage and show reduced cell-cycle entry. Surprisingly, and despite overlapping expression of both kinases, only ZAP-70 appears to promote sustained pre-TCR/TCR signaling during the DN4, immature single-positive, and double-positive stages of development before thymic selection occurs. ZAP-70 promotes survival and cell-cycle progression of developing thymocytes before positive selection, as also shown by in vivo anti-CD3 treatment of recombinase-activating gene 1-deficient mice. Our results establish a temporal separation of Syk family kinase function during early thymocyte development and a novel role for ZAP-70. We propose that pre-TCR signaling continues during DN4 and later stages, with ZAP-70 dynamically replacing Syk for continued pre-TCR signaling.
Palacios
Emil H
EH
Department of Medicine, the Rosalind Russell Medical Research Center for Arthritis, University of California-San Francisco, San Francisco, CA 94143, USA.
Weiss
Arthur
A
D000818:Animals; D016827:CD8 Antigens / Q000276:immunology; D005434:Flow Cytometry; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000235:genetics; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000502:physiology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016827:CD8 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D012313:RNA; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse