Tissue-specific targeting of cytokine unresponsiveness in transgenic mice.
The ubiquitous cellular distribution of certain cytokine receptors has hampered attempts to define the physiologically important cell-specific functions of cytokines in vivo. Herein, we report the generation of transgenic mice that express a dominant-negative IFN gamma receptor alpha chain mutant under the control of either the human lysozyme promoter or the murine lck proximal promoter, which display tissue-specific unresponsiveness in the macrophage or T cell compartments, respectively, to the pleiotropic cytokine, IFN gamma. We utilize these mice to identify previously undefined cellular targets of IFN gamma action in the development of a murine antimicrobial response and the mixed lymphocyte reaction. Moreover, we identify the macrophage as a critical responsive cell in manifesting the effects of IFN gamma in regulating CD4+ T helper subset development. These studies thus represent a novel approach to studying the cell-specific actions of an endogenously produced pleiotropic cytokine in vivo.
Dighe
A S
AS
Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Campbell
D
D
Hsieh
C S
CS
Clarke
S
S
Greaves
D R
DR
Gordon
S
S
Murphy
K M
KM
Schreiber
R D
RD
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects; D009928:Organ Specificity / Q000502:physiology; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects
D017471:Receptors, Interferon; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma