Plasmacytoid Dendritic Cells Are Key Regulators of Immune Tolerance

[摘要] Solid organ allograft rejection and many autoimmune disorders remain significant clinical problems despite the efficacy of current immunosuppressive (IS) drug treatments. Moreover, the side effects of global IS drugs that inhibit immune responses in a non-specific manner may leave the host susceptible to development of cancer and chronic infection. The need for antigen (Ag)-specific treatments to reduce or eliminate the need for IS drugs is merited in these cases.Dendritic cells (DC) are important Ag-presenting cells (APC) that mediate innate and adaptive immune responses, and have been widely investigated as potential cell-based therapeutics to bolster or supplant current IS drug treatments in transplantation and autoimmune diseases. Conventional (c)DC are the most potent APC, however, they can be modified and conditioned to instead modulate immune responses and promote Ag-specific tolerance. Plasmacytoid (p)DC, the primary cells that produce type I IFN and activate anti-viral immunity, are also recognized as holding significant tolerogenic potential. In this dissertation, I present novel data that support the tolerogenic function of pDC and highlight their inability to elicit strong immune responses in the absence of viral infection. pDC exhibit a more immature phenotype compared to cDC that correlates to their weak ability to stimulate T cells. Moreover, liver pDC are less mature compared to pDC in the spleen. They promote regulatory T cell function, suppress delayed-type hypersensitivity responses, and are critical for the spontaneous acceptance of murine liver allografts. My data show that the co-inhibitory molecule B7 homolog-1 (B7-H1) is important for the immune regulatory capacity of spleen and liver pDC, and that the cytokine IL-27 regulates critical inhibitory functions of liver pDC, including their expression of B7-H1 and their immune suppressive capacity in vitro and in vivo.In summary, my data provide evidence that pDC are an attractive target for development of cell-based therapies and identify novel mechanisms utilized by pDC to regulate immune reactivity. I have described for the first time that donor pDC contribute to the spontaneous acceptance of murine liver allografts, a discovery that has important implications for development of future therapeutics to promote immune tolerance, especially in solid organ transplantation.

[发布机构] the University of Pittsburgh