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Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells.

Gilliet M, Liu YJ - J. Exp. Med. (2002)

Bottom Line: Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-gamma upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-gamma, and no IL-4, IL-5, nor transforming growth factor (TGF)-beta.This inhibition was mediated by IL-10, but not by TGF-beta.IL-10-producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304, USA.

ABSTRACT
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)-gamma upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-gamma, and no IL-4, IL-5, nor transforming growth factor (TGF)-beta. 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-beta. 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.

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CD8 Tr cells do not suppress secondary responses. (A) 3-d secondary proliferation and (B) IFN-γ production by DC1-primed CD8 T cells induced by allogeneic monocytes plus CD8 Tr cells (1:1, 1:2, and 1:4 ratio). The stimulation index of naive CD8 T cells was calculated by the following formula: cpm [(DC1 − T + T reg + mono) − (T reg + mono)]/cpm (DC1 − T).
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fig8: CD8 Tr cells do not suppress secondary responses. (A) 3-d secondary proliferation and (B) IFN-γ production by DC1-primed CD8 T cells induced by allogeneic monocytes plus CD8 Tr cells (1:1, 1:2, and 1:4 ratio). The stimulation index of naive CD8 T cells was calculated by the following formula: cpm [(DC1 − T + T reg + mono) − (T reg + mono)]/cpm (DC1 − T).

Mentions: To test whether CD8 Tr cells could inhibit preactivated CD8 T cells, different numbers of DC2-primed CD8 Tr cells were added to a coculture of autologous DC1-preactivated CD8 T cells with APCs. As shown in Fig. 8, A and B , CD8 Tr cells were unable to suppress both the proliferative responses and the IFN-γ secretion of activated DC1-primed CD8 T cells. The increased proliferation and IFN-γ production detected in cultures with increasing numbers of CD8 Tr cells may simply reflect the additive effect of low levels of proliferation and IFN-γ production of CD8 Tr cells.


Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells.

Gilliet M, Liu YJ - J. Exp. Med. (2002)

CD8 Tr cells do not suppress secondary responses. (A) 3-d secondary proliferation and (B) IFN-γ production by DC1-primed CD8 T cells induced by allogeneic monocytes plus CD8 Tr cells (1:1, 1:2, and 1:4 ratio). The stimulation index of naive CD8 T cells was calculated by the following formula: cpm [(DC1 − T + T reg + mono) − (T reg + mono)]/cpm (DC1 − T).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193733&req=5

fig8: CD8 Tr cells do not suppress secondary responses. (A) 3-d secondary proliferation and (B) IFN-γ production by DC1-primed CD8 T cells induced by allogeneic monocytes plus CD8 Tr cells (1:1, 1:2, and 1:4 ratio). The stimulation index of naive CD8 T cells was calculated by the following formula: cpm [(DC1 − T + T reg + mono) − (T reg + mono)]/cpm (DC1 − T).
Mentions: To test whether CD8 Tr cells could inhibit preactivated CD8 T cells, different numbers of DC2-primed CD8 Tr cells were added to a coculture of autologous DC1-preactivated CD8 T cells with APCs. As shown in Fig. 8, A and B , CD8 Tr cells were unable to suppress both the proliferative responses and the IFN-γ secretion of activated DC1-primed CD8 T cells. The increased proliferation and IFN-γ production detected in cultures with increasing numbers of CD8 Tr cells may simply reflect the additive effect of low levels of proliferation and IFN-γ production of CD8 Tr cells.

Bottom Line: Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-gamma upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-gamma, and no IL-4, IL-5, nor transforming growth factor (TGF)-beta.This inhibition was mediated by IL-10, but not by TGF-beta.IL-10-producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, 901 California Avenue, Palo Alto, CA 94304, USA.

ABSTRACT
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)-gamma upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-gamma, and no IL-4, IL-5, nor transforming growth factor (TGF)-beta. 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-beta. 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.

Show MeSH
Related in: MedlinePlus