Publication Date:
2012-04-03
Description:
IL-17-producing CD4+ T helper cells (TH17) have been extensively investigated in mouse models of autoimmunity. However, the requirements for differentiation and the properties of pathogen-induced human TH17 cells remain poorly defined. Using an approach that combines the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, we describe here two types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL-17 and IFN-gamma, but no IL-10, whereas Staphylococcus aureus-specific TH17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1beta contributed to TH17 differentiation induced by both pathogens, but IL-1beta was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL-12 and to prime IL-17/IFN-gamma double-producing cells. In addition, IL-1beta inhibited IL-10 production in differentiating and in memory TH17 cells, whereas blockade of IL-1beta in vivo led to increased IL-10 production by memory TH17 cells. We also show that, after restimulation, TH17 cells transiently downregulated IL-17 production through a mechanism that involved IL-2-induced activation of STAT5 and decreased expression of ROR-gammat. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime TH17 cells that produce either IFN-gamma or IL-10, and identify IL-1beta and IL-2 as pro- and anti-inflammatory regulators of TH17 cells both at priming and in the effector phase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zielinski, Christina E -- Mele, Federico -- Aschenbrenner, Dominik -- Jarrossay, David -- Ronchi, Francesca -- Gattorno, Marco -- Monticelli, Silvia -- Lanzavecchia, Antonio -- Sallusto, Federica -- England -- Nature. 2012 Apr 26;484(7395):514-8. doi: 10.1038/nature10957.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland. christina.zielinski@charite.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22466287" target="_blank"〉PubMed〈/a〉
Keywords:
Antigen Presentation/immunology
;
Candida albicans/*immunology
;
Cell Differentiation
;
Down-Regulation
;
Humans
;
Immunologic Memory/immunology
;
Interferon-gamma/*biosynthesis
;
Interleukin-10/*biosynthesis
;
Interleukin-17/biosynthesis
;
Interleukin-1beta/*immunology
;
Interleukin-2/antagonists & inhibitors/immunology
;
Lymphocyte Activation
;
Nuclear Receptor Subfamily 1, Group F, Member 3/genetics/metabolism
;
STAT5 Transcription Factor/metabolism
;
Staphylococcus aureus/*immunology
;
Th17 Cells/cytology/*immunology/*metabolism/secretion
;
Tumor Necrosis Factor-alpha/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
