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Hepatic stroma-educated regulatory DCs suppress CD8+ T cell proliferation in mice
Qian Wang1,2, Hao He1, Dongwei Chen3
1Institute of Immunology, Taishan Medical University, Taian, Shandong, China.
Insights
Liver stromal cells educate dendritic cells (DCs) to suppress CD8+ T cell proliferation via nitric oxide, promoting liver tolerance. This discovery offers insights into immune regulation in the liver.
Area of Science:
- Immunology
- Hepatology
- Cell Biology
Background:
- Liver dendritic cells (DCs) are known to suppress CD4+ T cell responses.
- The role of liver DCs in regulating CD8+ T cell responses is less understood.
Purpose of the Study:
- To investigate how liver DCs suppress CD8+ T cell responses.
- To identify the mechanisms and factors involved in this suppression.
Main Methods:
- Bone marrow-derived mature DCs were incubated with liver stromal cells to generate liver stromal cell-educated DCs (LSed-DCs).
- Phenotypic characterization of LSed-DCs included assessing surface marker expression (CD11c, IA/IE, CD80, CD86, CD40, CD11b) and lifespan.
- CD8+ T cell proliferation, activation marker expression (CD25, CD69), and cytokine production (nitric oxide, IL-10) were analyzed.
- The role of soluble factors versus cell-cell contact in suppression was evaluated.
- Inhibition of nitric oxide synthase (NOS) with PBIT and IL-10 blockade were used to assess mechanisms.
- LSed-DCs were tested in a mouse model of autoimmune hepatitis to evaluate their effect on CD8+ T cell-mediated liver damage.
Main Results:
- LSed-DCs exhibited altered surface marker expression (reduced CD11c, IA/IE, CD80, CD86, CD40; increased CD11b) and a longer lifespan compared to mature DCs.
- LSed-DCs induced CD8+ T cell expression of CD25 and CD69 but inhibited their proliferation.
- Suppression was mediated by soluble factors, not cell-cell contact.
- LSed-DCs produced higher levels of nitric oxide (NO) and IL-10 than mature DCs.
- Inhibition of NOS with PBIT, but not IL-10 blockade, reversed the suppression of CD8+ T cell proliferation.
- LSed-DCs reduced CD8+ T cell-mediated liver damage in an autoimmune hepatitis model.
Conclusions:
- The liver stroma induces mature DCs to differentiate into regulatory DCs (LSed-DCs).
- LSed-DCs suppress CD8+ T cell proliferation primarily through nitric oxide production.
- These findings highlight a novel mechanism of immune regulation contributing to liver tolerance.
Abstract:
Liver dendritic cells (DCs) display immunosuppressive activities and inhibit the CD4+ T cell response. The present study assessed whether and how liver DCs suppress CD8+ T cells. We found that bone marrow-derived mature DCs incubated with liver stromal cells were characterized by a longer life span, reduced CD11c, IA/IE, CD80, CD86, and CD40 expression, and increased CD11b expression. These unique liver stromal cell-educated mature DCs (LSed-DCs) stimulated CD8+ T cells to express CD25 and CD69, but inhibited their proliferation. CD8+ T cell suppression depended on soluble factors released by LSed-DCs, but not cell-cell contact. Compared with mature DCs, LSed-DCs produced more nitric oxide and IL-10. Addition of a nitric oxide synthase inhibitor, PBIT, but not an IL-10-blocking mAb, reversed LSed-DC inhibition of CD8+ T cell proliferation. We also found that LSed-DCs reduced CD8+ T cell-mediated liver damage in a mouse model of autoimmune hepatitis. These results demonstrate that the liver stroma induces mature DCs to differentiate into regulatory DCs that suppress CD8+ T cell proliferation, and thus contribute to liver tolerance.
