Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

By M. Gilliet, Yong‐jun Liu. Journal of Experimental Medicine, 2002

701 citations recorded by the source corpus.

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/63fff28035202f3a1cdbd32b355d98f4f023f59c

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In Immunology

1. Yong‐jun Liu
2. G. Trinchieri
3. V. Kuchroo
4. H. Hammad
5. B. Lambrecht
6. A. O’Garra
7. M. Gilliet
8. M. Colonna

Citations in the corpus

• Human Plasmacytoid Dendritic Cells Activated by CpG Oligodeoxynucleotides Induce the Generation of CD4+CD25+ Regulatory T Cells1 (2004, background): “Naive CD8 T cells primed with CD154matured PDCs differentiated into IL-10-producing CD8 regulatory T (Treg) cells that strongly inhibit allospecific proliferation of naive CD8 T cells in a primary MLR (10).”
• The Development of Murine Plasmacytoid Dendritic Cell Precursors Is Differentially Regulated by FLT3-ligand and Granulocyte/Macrophage Colony-Stimulating Factor (2002, background): “Furthermore, it has been suggested that mature DCs derived from IPCs (pre-DC2) may induce adaptive immune responses with regulatory functions (27, 28).”
• Plasmacytoid dendritic cells in immunity (2004, background): “When CD40L-activated pDCs are cultured with allogeneic CD8 + T cells, the T cells show poor secondary proliferative and cytolytic activit”
• Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand (2007, background): “cells at a mature stage either activated by IL-3 plus CD40L or by TLR9 ligands (15, 16).”
• Essential Role of Lung Plasmacytoid Dendritic Cells in Preventing Asthmatic Reactions to Harmless Inhaled Antigen (2004, methodology): “CD11c CD11b B220 pDCs were sorted from Flt3L-cultured BM as described previously using a FACSDiVa ® flow cytometer (23, 28).”
• Tolerogenic dendritic cells and the quest for transplant tolerance (2007, background): “, and that pDCs activated with IL-3 and CD40 ligation induce regulatory CD8 + T cell”
• A dominant function for interleukin 27 in generating interleukin 10–producing anti-inflammatory T cells (2007, result): “In agreement with that hypothesis, CD8 + T cells primed with plasmacytoid DCs produce substantial IL-10 but little IFN-γ and inhibit the proliferation of naive CD8 T cells by an IL-10-dependent mechanis”
• The regulation of IL-10 production by immune cells (2010, background): “CD8 + T cells express IL-10 following TCR activation or interaction with CD40 ligand expressed by activated pDC”
• Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans (2006, background): “CD8 Tr1-like cells, which produce IL-10, have also been described (30, 31).”