First, pDC express the immunoregulatory enzyme IDO 75, 76, which promotes tryptophan catabolism, depleting

the tryptophan pool that T cells need to generate effective responses. IDO-expressing cells in TDLN of patients living with breast cancer correlate with worse clinical outcome 56. Similarly, studies performed in a mouse model of malignant melanoma have demonstrated that cells resembling pDC expressed IDO in TDLN 56 and activated Treg 57. Second, activated human pDC express ICOS ligand, which promotes the generation of IL-10-producing Treg from naïve T cells 77. In addition to infiltrating TDLN, pDC can be directly recruited to tumors by factors such as stromal-derived factor-1 30, 35 and induce IL-10-producing Treg. Moreover, human pDC can directly suppress T-cell responses through Olaparib this website the expression of granzyme B 78. The ability of pDC to induce Treg can also impact responses to HIV infection. Human pDC exposed to HIV in vitro express IDO and promote the differentiation of naïve CD4+ T cells into Treg that suppress proliferation of effector T cells 79 and impair DC maturation 80. Therefore, pDC accumulation during HIV infection may be detrimental. Although damaging in some cases, pDC-mediated recruitment of CTL and IFN-I secretion might be essential in the control of several infections, such as murine hepatitis virus, RSV, HSV-1 and HSV-2, where pDC depletion dramatically impairs host antiviral responses 44, 45, 48, 49, 81, 82. pDC

induction of Treg is also beneficial in many situations. Despite inducing tolerance to tumor cells, Phosphoprotein phosphatase pDC mediate tolerance to harmless Ag and alloAg through the induction of Treg 83–86. In homeostatic conditions,

self-reactive T cells are kept in check by Treg. Genetic defect of the Treg-specific transcription factor Foxp3 results in Treg deficiency and development of fatal autoimmune pathology 87. pDC also reside in the thymus 88, 89 and may directly participate in the generation of Treg in this organ 90, 91. Despite the negative impact pDC may have during HIV infection, evidence suggests that pDC may serve a protective role, at least early on during infection. Initially, it was observed that pDC numbers were dramatically reduced in the blood of patients chronically infected with HIV. Loss of pDC correlates with high viral loads, decreased numbers of CD4+ T cells and the onset of opportunistic infections 92–100. pDC stimulated in vitro with HIV secrete IFN-I and other immune mediators 101, 102 and can cross-present HIV-derived Ag to CD8+ T cells 103. HIV-activated pDC may also contribute to host responses by inducing DC maturation through the secretion of IFN-I and TNF-α 101. Furthermore, pDC-derived IFN-I induces an antiviral state and limits replication of HIV in CD4+ T cells 104, 105. pDC secretion of IFN-I also limits HCV replication in hepatocyte cell lines 106. Therefore, pDC may be capable of eliciting protective responses to HIV and HCV in vivo.