Interferon gamma signaling alters the function of T helper type 1 cells.
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 gamma receptor (IFN-gammaR), whereas Th1 cells do not express the second chain of the IFN-gammaR (IFN-gammaR2) and are therefore unresponsive to IFN-gamma. To determine whether the regulation of IFN-gammaR2 expression, and therefore IFN-gamma 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-gammaR2 is controlled by the CD2 promoter and enhancer. CD4(+) T cells from IFN-gammaR2 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-gamma 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-gammaR2 inhibits Th1 differentiation and function. Therefore, the acquisition of an IFN-gamma-unresponsive phenotype in Th1 cells plays a crucial role in the development and function of these cells.
Tau
G Z
GZ
Integrated Program in Cell, Molecular and Biophysical Studies, Columbia University, New York, New York 10032, USA.
von der Weid
T
T
Lu
B
B
Cowan
S
S
Kvatyuk
M
M
Pernis
A
A
Cattoretti
G
G
Braunstein
N S
NS
Coffman
R L
RL
Rothman
P B
PB
D000818:Animals; D000941:Antigens / Q000276:immunology; D002455:Cell Division; D016764:Cell Polarity; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D000096743:Interferon gamma Receptor
D000941:Antigens; D006433:Hemocyanins; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C086185:IFNGR2 protein, human; C490116:Ifngr2 protein, mouse; C032808:keyhole-limpet hemocyanin