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Original Article

Interferon Signaling Alters the Function of T Helper Type 1 Cells

^a Integrated Program in Cell, Molecular and Biophysical Studies, the
^b Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032
^c Department of Microbiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032
^d Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032
^e DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304
Department of Medicine, Division of Pulmonary, Allergy and Critical Care, P&S 8-425, Columbia University, 630 W. 168th St., New York, NY 10032.212-305-1870212-305-6982

One mechanism regulating the ability of different subsets of T helper (Th) cells to respond to cytokines is the differential expression of cytokine receptors. For example, Th2 cells express both chains of the interferon receptor (IFN-R), whereas Th1 cells do not express the second chain of the IFN-R (IFN-R2) and are therefore unresponsive to IFN-. To determine whether the regulation of IFN-R2 expression, and therefore IFN- responsiveness, is important for the differentiation of naive CD4⁺ T cells into Th1 cells or for Th1 effector function, we generated mice in which transgenic (TG) expression of IFN-R2 is controlled by the CD2 promoter and enhancer. CD4⁺ T cells from IFN-R2 TG mice exhibit impaired Th1 polarization potential in vitro. TG mice also display several defects in Th1-dependent immunity in vivo, including attenuated delayed-type hypersensitivity responses and decreased antigen-specific IFN- production. In addition, TG mice mount impaired Th1 responses against Leishmania major, as manifested by increased parasitemia and more severe lesions than their wild-type littermates. Together, these data suggest that the sustained expression of IFN-R2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-–unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.

Key Words: T helper type 1 cells • interferon type II • interferon receptors • hypersensitivity, delayed • cytokines

© 2000 The Rockefeller University Press

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