Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development.
The murine cytokine thymic stromal lymphopoietin (TSLP) supports the development of B220+ IgM+ immature B cells and induces thymocyte proliferation in vitro. Human TSLP, by contrast, activates CD11c+ dendritic cells, but not B or T cells. Recent studies have demonstrated that the receptor for TSLP consists of a heterodimer of the interleukin 7 (IL-7) alpha chain and a novel protein that resembles the hematopoietic cytokine receptor common gamma chain. We examined signal transduction by the gamma-like chains using chimeric receptor proteins. The cytoplasmic domain of the human, but not of the murine, gamma-like chain, activates Jak2 and Stat5 and supports the proliferation of hematopoietic cell lines. In order to assess the role of the murine gamma-like chain in vivo, we generated gamma-like chain-deficient mice. Receptor-deficient mice are unresponsive to TSLP but exhibit no obvious phenotypic defects. In particular, hematopoietic cell development appeared normal. B-cell development, including the IgM+ compartment, was unaffected by loss of the TSLP pathway, as were T lymphopoiesis and lymphocyte proliferation in vitro. Cytokine receptors that utilize the common gamma chain signal through the lymphocyte-specific kinase Jak3. Mice deficient in Jak3 exhibit a SCID phenotype but harbor a residual B220+ splenic lymphocyte population. We demonstrate here that this residual lymphocyte population is lost in mice lacking both the gamma-like chain and Jak3.
Carpino
Nick
N
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Thierfelder
William E
WE
Chang
Ming-shi
MS
Saris
Chris
C
Turner
Steven J
SJ
Ziegler
Steven F
SF
Ihle
James N
JN
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins; D066298:In Vitro Techniques; D053616:Janus Kinase 3; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018121:Receptors, Cytokine / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000094632:Thymic Stromal Lymphopoietin
C498762:CRLF2 protein, human; D016207:Cytokines; D018076:DNA, Complementary; D007136:Immunoglobulins; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; C410591:Tslpr protein, mouse; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D000094632:Thymic Stromal Lymphopoietin