CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease

Nature Immunology 9:1253-60 (2008)

Speaker: Wen-Ling Yeh (葉玟伶)                             Time: 13:00~14:00 May. 13, 2009

Commentator: Dr. Pin Ling (凌斌 老師)               Place: Room 601

Abstract:

        Dentritic cell (DC) is the bridge between innate and adaptive immunity. After sensing pathogen molecules, DCs activate and mature with up-regulation of costimulatory molecules. Besides, DCs play an important role in self-tolerance by present self-antigen to T cells and induce self-reactive T cell apoptosis or anergy.^[1]  Thus, DC-based treatments were used for inflammation, autoimmune disease, and graft-versus-host disease (GVHD).^[2] One lineage called plasmacytoid dentritic cells (pDCs) was reported to mediate oral tolerance function alleviating intestinal and systemic inflammatory diseases.^[3] In this paper, the authors found that CCR9 down-regulation of pDCs which activated by TLR7 and TLR9 ligands is a marker of mature pDCs. They also noted more migration of CCR9⁺ pDCs to CCL25 attraction compare to CCR9^- pDCs. Moreover, coculture with the CCR9⁺ pDCs significantly increased the amount of CD4⁺CD25^- Foxp3⁺ effector T cells and suppressed the proliferation of OVA specific effector T cells after OVA challenge. In GVHD induction model, transplant of bone marrow, effector T cells from BALB/c and CCR9⁺ pDCs from C57BL/6 mice to naive C57BL/6 mice rescued the survival rate and clinical signs such as weight loss, diarrhea and hunched posture compared to CCR9^- pDCs transplantation. Furthermore, coinjection of CCR9⁺ pDC with effector T cells suppressed the generation of IL-17-producing T cells but enhanced the generation of IFN-γ-producing T cells in peripheral lymph nodes and Spleen. These findings suggest that CCR9⁺ pDC have long-term suppression of GVHD by transforming effector T cells to regulatory T cells. These CCR9⁺ pDC with potential of immunosuppression could be used to reduce inflammatory disease and increase the success rate of transplantion.

References:

1. Steinman, R.M, et al. 2003. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711

2. Katsuaki Sato, et al. 2003. Regulatory Dendritic Cells Protect Mice from Murine Acute Graft-versus-Host Disease and Leukemia Relapse. Immunity, Vol. 18, 367–379

3. Anne Goubier, et al. 2008. Plasmacytoid Dendritic Cells Mediate Oral Tolerance. Immunity 29, 464–475