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Microenvironment-Dependent Requirement of STAT4 for the Induction of P-Selectin Ligands and Effector Cytokines on CD4⁺ T Cells in Healthy and Parasite-Infected Mice¹

Uta Syrbe^2,*,, Ute Hoffmann^*, Kerstin Schlawe^*, Oliver Liesenfeld, Klaus Erb^3, and Alf Hamann^*

^* Charité, Campus Mitte, Experimentelle Rheumatologie, c/o Deutsches Rheumaforschungszentrum, Berlin, Germany; Charité, Campus Benjamin Franklin, Medizinische Klinik I, Berlin, Germany; Charité, Campus Benjamin Franklin, Institut für Mikrobiologie und Hygiene, Berlin, Germany; and Klaus Erb, Zentrum für Infektionsforschung, Universität Würzburg, Würzburg, Germany

T effector cells require selectin ligands to migrate into inflamed regions. In vitro, IL-12 promotes induction of these ligands as well as differentiation of CD4⁺ T cells into IFN--producing Th1 but not Th2 cells. STAT4 is strongly involved in these processes. However, the presence of selectin ligands on various T effector cell subsets in vivo points to more complex regulatory pathways. To clarify the role of the IL-12/STAT4 signaling pathway, we analyzed the impact of STAT4 deficiency on the expression of P-selectin ligands (P-lig) on CD4⁺ T cells in vitro and in vivo, including conditions of infection. In vitro, we found significant expression of P-lig upon activation not only in the presence, but also in the absence, of IL-12, which was independent of STAT4. TGF-, an alternative inducer of selectin ligands in human T cells, was not effective in murine CD4⁺ T cells, suggesting a role of additional signaling pathways. In vivo, a significant impact of STAT4 for the generation of P-lig⁺CD4⁺ T cells was observed for cells from peripheral lymph nodes, but not for those from spleen or lung. However, upon infection with the Th2-inducing parasite Nippostrongylus brasiliensis, P-lig expression became dependent on STAT4 signaling. Interestingly, also the frequency of IL-4-producing cells was greatly diminished in absence of STAT4. These data reveal a hitherto unknown contribution of STAT4 to the generation of Th2 cells in parasite infection and suggest that signals inducing inflammation-seeking properties in vivo vary depending on environmental conditions, such as type of organ and infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 366 and SY 31/2-1.

² Address correspondence and reprint requests to Dr. Uta Syrbe, Experimental Rheumatology, c/o Deutsches Rheumaforschungszentrum, Schumannstrasse 21/22, 10117 Berlin, Germany. E-mail address: syrbe{at}drfz.de

³ Current address: Boehringer Ingelheim Pharma, 88397 Biberach an der Riss, Germany.

⁴ Abbreviations used in this paper: PSGL-1, P-selectin glycoprotein ligand 1; P-lig, P-selectin ligand; FucT, fucosyltransferase; C2GlcNAT, core 2 1,6-glucosaminyltransferase; MFI, mean fluorescence intensity.

This article has been cited by other articles:

				S. Jennrich, B. A. Ratsch, A. Hamann, and U. Syrbe Long-Term Commitment to Inflammation-Seeking Homing in CD4+ Effector Cells J. Immunol., June 15, 2007; 178(12): 8073 - 8080. [Abstract] [Full Text] [PDF]