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A new look at Syk in alpha beta and gamma delta T cell development using chimeric mice with a low competitive hematopoietic environment.
Journal of Immunology
The Syk protein tyrosine kinase (PTK) is essential for B, but not T or NK, cell development, although certain T cell subsets (i.e., gamma delta T cells of intestine and skin) appear to be dependent on Syk. In this report, we have re-evaluated the role of Syk in T cell development in hematopoietic chimeras generated by using Syk-deficient fetal liver hematopoietic stem cells (FL-HSC). We found that Syk-/- FL-HSC were vastly inferior to wild-type FL-HSC in reconstituting T cell development in recombinant-activating gene 2 (RAG2)-deficient mice, identifying an unexpected and nonredundant role for Syk in this process. This novel function of Syk in T cell development was mapped to the CD44-CD25+ stage. According to previous reports, development of intestinal gamma delta T cells was arrested in Syk-/- -->RAG2-/- chimeras. In striking contrast, when hosts were the newly established alymphoid RAG2 x common cytokine receptor gamma-chain (RAG2/gamma c) mice, Syk-/- chimeras developed intestinal gamma delta T cells as well as other T cell subsets (including alpha beta T cells, NK1.1+ alpha beta T cells, and splenic and thymic gamma delta T cells). However, all Syk-deficient T cell subsets were reduced in number, reaching about 25-50% of controls. These results attest to the utility of chimeric mice generated in a low competitive hematopoietic environment to evaluate more accurately the impact of lethal mutations on lymphoid development. Furthermore, they suggest that Syk intervenes in early T cell development independently of ZAP-70, and demonstrate that Syk is not essential for the intestinal gamma delta T cell lineage to develop.
Animals, Cell Differentiation/genetics, Cell Differentiation/immunology, DNA-Binding Proteins/deficiency, DNA-Binding Proteins/genetics, Enzyme Precursors/deficiency, Enzyme Precursors/genetics, Fetal Tissue Transplantation/immunology, Hematopoietic Stem Cells/cytology, Hematopoietic Stem Cells/enzymology, Intestinal Mucosa/cytology, Intestinal Mucosa/immunology, Intracellular Signaling Peptides and Proteins, Liver Transplantation/immunology, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Protein-Tyrosine Kinases/deficiency, Protein-Tyrosine Kinases/genetics, Radiation Chimera/immunology, Receptors, Antigen, T-Cell, alpha-beta/genetics, Receptors, Antigen, T-Cell, gamma-delta/genetics, Receptors, Cytokine/deficiency, Receptors, Cytokine/genetics, T-Lymphocyte Subsets/cytology, T-Lymphocyte Subsets/enzymology
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