The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/10/1147/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 8, October 18, 1999 1147-1154

Original Article

Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon {gamma} Production in Human T Lymphocytes

Jun-ichi Kashiwakuraa, Noboru Suzukia, Hiroko Nagafuchia, Mitsuhiro Takenoa, Yuko Takebaa, Yoshihiro Shimoyamaa, and Tsuyoshi Sakanea

a Department of Immunology and the Department of Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan
Depts. of Immunology and Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.81-44-975-434781-44-977-8111 ext. 4014

t2sakane{at}marianna-u.ac.jp

Differentiation of human T cells into T helper (Th)1 and Th2 cells is vital for the development of cell-mediated and humoral immunity, respectively. However, the precise mechanism responsible for the Th1 cell differentiation is not fully clarified. We have studied the expression and function of Txk, a member of the Tec family of nonreceptor tyrosine kinases. We found that Txk expression is restricted to Th1/Th0 cells with IFN-{gamma} producing potential. Txk transfection of Jurkat T cells resulted in a several-fold increase of IFN-{gamma} mRNA expression and protein production; interleukin (IL)-2 and IL-4 production were unaffected. Antisense oligodeoxynucleotide of Txk specifically inhibited IFN-{gamma} production of normal peripheral blood lymphocytes, antigen-specific Th1 clones, and Th0 clones; IL-2 and IL-4 production by the T cells was unaffected. Txk cotransfection led to the enhanced luciferase activity of plasmid (p)IFN-{gamma} promoter/enhancer (pIFN-{gamma}[-538])-luciferase–transfected Jurkat cells upon mitogen activation. Txk transfection did not affect IL-2 and IL-4 promoter activities. Thus, Txk specifically upregulates IFN-{gamma} gene transcription. In fact, Txk translocated from cytoplasm into nuclei upon activation and transfection with a mutant Txk expression plasmid that lacked a nuclear localization signal sequence did not enhance IFN-{gamma} production by the cells, indicating that nuclear localization of Txk is obligatory for the enhanced IFN-{gamma} production. In addition, IL-12 treatment of peripheral blood CD4+ T cells enhanced the Txk expression, whereas IL-4 treatment completely inhibited it. These results indicate that Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-{gamma} production by the cells through Th1 cell–specific positive transcriptional regulation of the IFN-{gamma} gene.

Key Words: Txk • gene transcription • T helper 1/T helper 2 cells • human • interferon {gamma}

1used in this paper: CAT, chloramphenicol acetyl transferase; ODN, oligodeoxynucleotide; p, plasmid; RSV, Rous sarcoma virus; RT, reverse transcription; SH, src homology

© 1999 The Rockefeller University Press


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