Interleukin-2 inhibits FMS-like tyrosine kinase 3 receptor ligand (flt3L)-dependent development and function of conventional and plasmacytoid dendritic cells

Steady-state development of plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) requires the ligand for FMS-like tyrosine kinase 3 receptor (flt3L), but little is known about how other cytokines may also control this process. In this study, we show that IL-2 inhibits the deve...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-02, Vol.108 (6), p.2408-2413
Main Authors: Lau-Kilby, Annie W., Kretz, Cosima C., Pechhold, Susanne, Price, Jeffrey D., Dorta, Stephanie, Ramos, Haydee, Trinchieri, Giorgio, Tarbell, Kristin V., Steinman, Ralph M.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - immunology
Biological Sciences
Bone marrow
Bone Marrow Cells - cytology
Bone Marrow Cells - immunology
Bone Marrow Cells - metabolism
Cell culture
Cell Proliferation
Cultured cells
Cytokines
Data processing
Dendritic cells
Dendritic Cells - cytology
Dendritic Cells - immunology
Dendritic Cells - metabolism
Development
Diabetes
Diabetes mellitus
Flt3 protein
FLT3L protein
Immunological tolerance
Interleukin 2
Interleukin 2 receptors
Interleukin-2 - genetics
Interleukin-2 - immunology
Interleukin-2 - metabolism
Interleukin-2 Receptor alpha Subunit - genetics
Interleukin-2 Receptor alpha Subunit - immunology
Interleukin-2 Receptor alpha Subunit - metabolism
Interleukin-2 Receptor beta Subunit - genetics
Interleukin-2 Receptor beta Subunit - immunology
Interleukin-2 Receptor beta Subunit - metabolism
Kinases
Ligands
Lymphocytes T
Membrane Proteins - genetics
Membrane Proteins - immunology
Membrane Proteins - metabolism
Mice
Mice, Inbred NOD
Mice, Transgenic
Monocytes
Plasma Cells - cytology
Plasma Cells - immunology
Plasma Cells - metabolism
Progenitor cells
Receptor mechanisms
Receptors
Rodents
Signal transduction
Signal Transduction - immunology
Spleen
Stem cells
Studies
T cell receptors
T lymphocytes
T lymphoid precursor cells
T-Lymphocytes - cytology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Type 1 diabetes mellitus
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Summary:Steady-state development of plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) requires the ligand for FMS-like tyrosine kinase 3 receptor (flt3L), but little is known about how other cytokines may also control this process. In this study, we show that IL-2 inhibits the development of both pDCs and cDCs from bone marrow cells under flt3L stimulation, by acting on lineage¯flt3⁺ precursors. This inhibition of DC development by IL-2 requires IL-2Rα and IL2Rß. IL-2Ra is specifically expressed in one stage of the DC precursor: the monocyte and DC progenitors (MDPs). Furthermore, more MDPs are found in flt3L-stimulated bone marrow cultures when IL-2 is present, suggesting that IL-2 may be inhibiting DC development at the MDP stage. Consistent with our in vitro findings, we observe that nonobese diabetic (NOD) mice, which express less IL-2 compared with diabetes-resistant NOD.Idd3/5 mice, have more splenic pDCs. Additionally, DCs developed in vitro in the presence of flt3L and IL-2 display reduced ability to stimulate T-cell proliferation compared with DCs developed in the presence of flt3L alone. Although the addition of IL-2 does not increase the apoptosis of DCs during their development, DCs developed in the presence of IL-2 are more prone to apoptosis upon interaction with T cells. Together our data show that IL-2 can inhibit both the development and the function of DCs. This pathway may have implications for the loss of immune tolerance: Reduced IL-2 signaling may lead to increased DC number and T-cell stimulatory capacity.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1009738108