A new look at Syk in alpha beta and gamma delta T cell development using chimeric mice with a low competitive hematopoietic environment.
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.
Colucci
F
F
Institut National de la Santé et de la Recherche Médicale U429, Hôpital Necker-Enfants Malades, Paris, France. cecco@pasteur.fr
Guy-Grand
D
D
Wilson
A
A
Turner
M
M
Schweighoffer
E
E
Tybulewicz
V L
VL
Di Santo
J P
JP
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004792:Enzyme Precursors / Q000172:deficiency* / Q000235:genetics*; D016332:Fetal Tissue Transplantation / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D016031:Liver Transplantation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics*; D011828:Radiation Chimera / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology
D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D018121:Receptors, Cytokine; C064655:V(D)J recombination activating protein 2; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse