Requirement for Jak3 in mature T cells: its role in regulation of T cell homeostasis.
The tyrosine kinase Jak3 plays a key role in transducing signals from the IL-2, -4, -7, -9, and -15 receptors. Mice lacking Jak3 exhibit a profound, early block in both B and T cell development. To examine the mechanisms whereby Jak3 influences T cell function, we have reconstituted thymic development in Jak3-/- animals by introducing a Jak3 transgene in which expression was driven by the lck proximal promoter. Thymic reconstitution required Jak3 kinase activity, as catalytically inactive Jak3 did not restore early thymic development. Furthermore, the thymus-restricted expression pattern of the transgene allowed us to assess the requirement for Jak3 in peripheral T cells. In these mice, loss of Jak3 expression was associated with a failure to proliferate in response to antigen receptor crosslinking, the accumulation of T cells manifesting an activated cell surface phenotype, and an increased CD4/CD8 ratio among peripheral T cells, all of which are characteristics that were observed in Jak3-/- animals. Finally, we present data which suggest that peripheral T cells proliferate more rapidly in vivo and also undergo apoptosis more rapidly, upon loss of Jak3. Hence Jak3 exerts effects on mature peripheral T lymphocytes, as well as on thymocytes, resulting in the proper maintenance of circulating, quiescent cells.
Sohn
S J
SJ
Howard Hughes Medical Institute, University of Washington, Seattle 98195, USA.
Forbush
K A
KA
Nguyen
N
N
Witthuhn
B
B
Nosaka
T
T
Ihle
J N
JN
Perlmutter
R M
RM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016516:CD4-CD8 Ratio; D002384:Catalysis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D016130:Immunophenotyping; D053616:Janus Kinase 3; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000502:physiology; D019076:Transgenes / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3