Mutation of Tec family kinases alters T helper cell differentiation.
The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation.
Schaeffer
E M
EM
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yap
G S
GS
Lewis
C M
CM
Czar
M J
MJ
McVicar
D W
DW
Cheever
A W
AW
Sher
A
A
Schwartzberg
P L
PL
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050990:GATA3 Transcription Factor; D007073:Immunoglobulin E / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D012555:Schistosomiasis mansoni / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D007073:Immunoglobulin E; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase