The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/1191/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 6, September 21, 1998 1191-1196

Brief Definitive Reports

A Signal Transducer and Activator of Transcription (Stat)4-independent Pathway for the Development of T Helper Type 1 Cells

Mark H. Kaplan*, Andrea L. Wurster*, and Michael J. Grusby*,{ddagger}

From the * Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115; and the {ddagger} Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6–/– lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4–/– lymphocytes, T cells from Stat4, Stat6–/– mice produce significant amounts of interferon (IFN)-{gamma} when activated in vitro. Although Stat4, Stat6–/– lymphocytes produce less IFN-{gamma} than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-{gamma}–secreting cells can be generated from cultures of Stat4, Stat6–/– lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6–/– mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

Key Words: T cell differentiation • interleukin 4 • interleukin 12 • signal transducer and activator of transcription

Address correspondence to Michael J. Grusby, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115. Phone: 617-432-1240; Fax: 617-432-0084; E-mail: grusby{at}mbcrr.harvard.edu Mark Kaplan's present address is Walther Oncology Center, Indiana University, Indianapolis, IN 46202.

M.H. Kaplan is a Special Fellow and M.J. Grusby is a Scholar of the Leukemia Society of America. This work was supported by a grant from the National Institutes of Health to M.J. Grusby (RO1 AI-40171), and by a gift from the Mathers Foundation.


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