Microenvironment-dependent requirement of STAT4 for the induction of P-selectin ligands and effector cytokines on CD4+ T cells in healthy and parasite-infected mice.
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-gamma-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-beta, 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.
Syrbe
Uta
U
Charité, Campus Mitte, Experimentelle Rheumatologie, c/o Deutsches Rheumaforschungszentrum, Schumannstrasse 21/22, 10117 Berlin, Germany. syrbe@drfz.de
Hoffmann
Ute
U
Schlawe
Kerstin
K
Liesenfeld
Oliver
O
Erb
Klaus
K
Hamann
Alf
A
D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009559:Nippostrongylus / Q000276:immunology; D019007:P-Selectin / Q000096:biosynthesis*; D010273:Parasitic Diseases, Animal / Q000276:immunology*; D050797:STAT4 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D008024:Ligands; D019007:P-Selectin; D050797:STAT4 Transcription Factor; D018664:Interleukin-12