TY - JOUR
T1 - Interleukin-10 Production by Th1 Cells Requires Interleukin-12-Induced STAT4 Transcription Factor and ERK MAP Kinase Activation by High Antigen Dose
AU - Saraiva, Margarida
AU - Christensen, Jillian R.
AU - Veldhoen, Marc
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
AU - O'Garra, Anne
N1 - Funding Information:
We thank C. Atkins, A. Rae, G. Preece, and N. Biboum for assistance in flow cytometry and M. Holman for the help with the in vivo experiments. We also thank the National Institute for Medical Research (NIMR) Biological Services for their animal husbandry and breeding. We specially thank G. Trinchieri (National Cancer Institute, National Institutes of Health, USA), F. Barrat (Dynavax, CA, USA), B. Stockinger, S. Ley, and G. Kassiotis (NIMR, Mill Hill, UK) for critically reading the manuscript and offering helpful advice. We thank P. Cohen and N. Shpiro, University of Dundee, for their generosity in providing MAP kinase PD184352 and CT99021 inhibitor reagents, as well as advice on their use, and thank P. Cohen also for providing critical advice. This work was supported by the Medical Research Council, UK, (M.S., J.R.C., M.V., and A.O.G.) and Howard Hughes Medical Institute (K.M.M. and T.L.M.).
PY - 2009/8/21
Y1 - 2009/8/21
N2 - CD4+ T cells producing interleukin-10 (IL-10) and interferon-γ (IFN-γ) are reported in chronic infections. However, the signals that direct the development of IL-10-producing T helper 1 (Th1) cells are undefined. We showed that development of IL-10-producing Th1 cells required high T cell receptor (TCR) ligation, sustained ERK1 and ERK2 MAP kinases phosphorylation, and IL-12-induced STAT4 transcription factor activation. Repeated TCR triggering led to enhanced IL-10 production by Th1 cells, and continued IL-12 action and high-dose TCR signaling were required for the development and maintenance of IL-10-producing Th1 cells. Although Th1, Th2, and Th17 cells require the activation of distinct STATs for their differentiation, activation of ERK1 and ERK2 was a common requirement for production of IL-10 by all Th cell subsets. IL-10 expression also correlated with c-maf expression. Despite having distinct functions in protection against pathogens, all Th cells share the important task of controlling overexuberant immune responses by means of IL-10 production.
AB - CD4+ T cells producing interleukin-10 (IL-10) and interferon-γ (IFN-γ) are reported in chronic infections. However, the signals that direct the development of IL-10-producing T helper 1 (Th1) cells are undefined. We showed that development of IL-10-producing Th1 cells required high T cell receptor (TCR) ligation, sustained ERK1 and ERK2 MAP kinases phosphorylation, and IL-12-induced STAT4 transcription factor activation. Repeated TCR triggering led to enhanced IL-10 production by Th1 cells, and continued IL-12 action and high-dose TCR signaling were required for the development and maintenance of IL-10-producing Th1 cells. Although Th1, Th2, and Th17 cells require the activation of distinct STATs for their differentiation, activation of ERK1 and ERK2 was a common requirement for production of IL-10 by all Th cell subsets. IL-10 expression also correlated with c-maf expression. Despite having distinct functions in protection against pathogens, all Th cells share the important task of controlling overexuberant immune responses by means of IL-10 production.
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=68649116551&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2009.05.012
DO - 10.1016/j.immuni.2009.05.012
M3 - Article
C2 - 19646904
AN - SCOPUS:68649116551
SN - 1074-7613
VL - 31
SP - 209
EP - 219
JO - Immunity
JF - Immunity
IS - 2
ER -