Abstract
CD4(+)Foxp3(+) T regulatory cells (Tregs) display phenotypic and functional plasticity that is regulated by cytokines and other immune cells. Previously, we determined that during co-culture with CD4(+)CD25(-) T cells and antigen presenting cells, Tregs produced IL-17. Here, we investigated the mechanisms underlying the differentiation of IL-17-producing Treg (Tr17) cells and their molecular and functional properties. We determined that during stimulation via TCR/CD3 and CD28, the combination of IL-1β and IL-2 was necessary and sufficient for the generation of Tr17 cells. Tr17 cells expressed Runx1 transcription factor, which was required for sustained expression of Foxp3 and RORγt and for production of IL-17. Surprisingly, Tr17 cells also expressed Runx3, which regulated transcription of perforin and granzyme B thereby mediating cytotoxic activity. Our studies indicate that Tr17 cells concomitantly express Foxp3, RORγt, Runx1 and Runx3 and are capable of producing IL-17 while mediating potent suppressive and cytotoxic function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / immunology*
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Core Binding Factor Alpha 2 Subunit / metabolism
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Core Binding Factor Alpha 3 Subunit / genetics
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Core Binding Factor Alpha 3 Subunit / immunology*
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Core Binding Factor Alpha 3 Subunit / metabolism
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Flow Cytometry
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Gene Expression
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Granzymes / genetics
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Granzymes / immunology
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Granzymes / metabolism
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Immunophenotyping
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-17 / metabolism
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Interleukin-1beta / pharmacology
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Interleukin-2 / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
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Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Perforin / genetics
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Perforin / immunology
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Perforin / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
Substances
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Core Binding Factor Alpha 2 Subunit
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Core Binding Factor Alpha 3 Subunit
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-17
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Interleukin-1beta
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Interleukin-2
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Perforin
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Granzymes