CONDITIONAL DELETION OF GATA-3 REVEALS ITS CRITICAL ROLE IN TH1/TH2 RESPONSES

Authors: ZHU, JINFANG - NIH, BETHESDA, MD; MIN, BOOKI - " "; HU-LI, JANE - " "; WATSON, CYNTHIA - " "; GRINBERG, ALEX - " "; WANG, QUI - UCSF, SAN FRANC.,CA; KILLEEN, NIGEL - " "; Urban, Joseph; GUO, LIYING - NIH, BETHESDA, MD; PAUL, WILLIAM - " "

Submitted to: Nature Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/1/2004
Publication Date: 11/15/2004
Citation: Zhu, J., Min, B., Hu-Li, J., Watson, C., Grinberg, A., Wang, Q., Killeen, N., Urban Jr, J.F., Guo, L., Paul, W. 2004. Conditional deletion of gata-3 reveals its critical role in th1/th2 responses. Nature Immunology. 5(11):1157-1165.

Interpretive Summary: Specific components of the immune response mediate host protection against worm parasites and allergic responses. Parasitic infections have major impact on efficient production of healthy animals and affect the general health of children in many less developed countries worldwide. A central molecular in activation of this response is a protein messenger molecule called IL-4 that primes lymphocytes to become Th2 cells which are key cellular regulators of protection. Once IL-4 is produced, there are down stream mechanisms that initiate a series of reactions that can lead to protective immunity against parasitic worm infections or, in the case of areas of the world without parasites, exacerbated responses to common allergens. This report is the first report to show that elimination of the gene expression target called GATA-3 deletes the down stream effects of IL-4 on immunity to parasitic infection. This information can be used to more efficiently regulate the response to enhance resistance or reduce the potentially negative side effects of an unregulated response to worms or allergens. This information will be primarily of interest to scientific investigators that study protective immunity to worm infections and the expression of allergic diseases. It can also be used to design novel strategies to monitor and regulate the level of the response through dietary interventions.

Technical Abstract: GATA-3 expression is strikingly associated with Th2 differentiation but genetic evidence for its role in this process has been lacking. A conditional GATA-3 knockout was generated. In vitro deletion of GATA-3 diminished both IL-4 dependent and IL-4 independent Th2 cell differentiation; without GATA-3, Th1 differentiation occurred in the absence of IL-12 and IFN-gamma. GATA-3 is important in Th2 but not Th1 cell proliferation. Deleting GATA-3 from established Th2 cells abolished IL-5 and IL-13 but not IL-4 production. In vivo deletion of GATA-3 using OX40-cre markedly diminished the development of IL-4, IL-5 and IL-13-producing cells and allowed the development of IFN-gamma-producing cells, prevented IgE induction and blocked clearance of worms in mice infected with Nippostrongylus brasiliensis. Thus, GATA-3 is a major physiologic controller of Th1/Th2 differentiation.