CCL20 is expressed by keratinocytes in the skin and by melanoma cells, suggesting that this CCL20/CCR6 conversation is involved in the pDC migration process from the blood to the tumor (145C147). 26, 76C78). The nuances of pDCs antigen processing and presentation have recently been reviewed by Guery and Hugues (42) and Nierkens et al. (79). Here, we focus our attention on how pDC cell surface receptors may skew T cell function (Physique ?(Figure3).3). Freshly isolated (immature) pDCs are known to induce CD4+ T cell anergy presumably because they lack co-stimulatory molecules; conversely, activated pDC clearly induce a broad spectrum of T cell differentiation, for example, Th1, Th2, Th17, and Treg, based on the cytokines secreted and cell surface proteins expressed (21, 80C84). Like mDCs, activated pDC express high levels of MHC molecules and the co-stimulatory molecules CD80 (B7-1), CD86 (B7-2), and CD83 to present antigens and fully license and activate T cells (5, 6). Several studies have exhibited that (virally) matured pDCs, through the release of cytokines, mostly induce a Th1 phenotype (IFN-/Il-12 in response to CpG, computer virus) but Th2 (IL-4) and Th17 (IL-17) skewing has also been reported when pDC are activated with IL-3 or CD40 and TLR7 ligands, respectively (82, 85C87). Furthermore IL-21 (produced in the LN) was shown to trigger the release of Granzyme B by TLR-activated pDCs thereby dampening CD4+ T cell proliferation (88). Together these studies show how pDCs may regulate immune responses. Apart from cytokines released by pDCs, several pDC surface receptors may directly affect T cell skewing and function, including the inducible T-cell co-stimulator ligand (ICOSL). pDCs express ICOSLG when activated by CpG-(A, B, and C) IL-3/CD40L or computer virus (Flu/HSV) (83). ICOSLG is the ligand for the T-cell-specific cell surface receptor inducible costimulator (ICOS) and has been shown to trigger naive CD4+ T cells to produce IL-10 during both pDC Th1 or Th2 skewing in response to CpG/virally or IL-3/CD40L-matured pDCs, respectively (83, 84). It has been suggested that ICOSL-activated pDCs generate IL-10 producing Tregs to dampen immune responses, preventing excessive inflammation (83). Furthermore TLR activated, but not resting pDCs and mDCs, express programed death receptor-ligand 1 (PD-L1), which may induce T cells anergy/suppresses T cell activation by binding to its receptor, program death ligand 1 (PD1), which is usually expressed by T cells (89, 90). The immunosuppressive effect of PD-L1 has been confirmed by using blocking antibodies on DCs, and additionally in follow-up studies where blocking the PD-L1/PD1 conversation lead to enhanced tumor-specific T cell growth and activation (6, 91, 92). The surface receptor OX40, which is usually expressed on IL-3 activated pDCs, can induce a Th2 T cell response resulting in IL-4, IL-5, and IL-13 release by CD4+ T cells (93, 94). Open in a separate window Physique 3 Ligand/receptor FK-506 (Tacrolimus) paring of a pDC with a T cell and the maturation state/activation stimuli associated with ligand or receptor expression around the pDC surface. Furthermore, after stimulation either with synthetic TLR7 and 9 agonists or with the natural TLR7 agonists, like influenza computer virus or UV-inactivated HSV type 1(HSVUV) pDCs can induce programed cell death/apoptosis, by expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (74, 95, 96). TRAIL expression on pDCs uniquely correlates with viral load, and the capacity to kill HIV-infected CD4+ T cells by IRF7 binding to the TRAIL receptor, a process described as TRAIL-dependent pDC-mediated killing (97). However, given the very limited cell numbers, it remains to FK-506 (Tacrolimus) be seen how important TRAIL+ pDCs are in clearing a viral contamination via the direct killing of infected cells (97, FK-506 (Tacrolimus) 98). Another surface molecule expressed on TLR-activated pDCs that may affect T cell function is the lectin-like transcript 1 (LLT1), which in addition to activated pDCs, is expressed by most activated lymphocytes (including B cells, T cells, and NK cells) and mature monocyte-derived DCs (99). LLT1 is usually a ligand of CD161 (NKR-P1A), which is usually expressed by subsets of T cells (e.g., Th1, Th17, and a.