Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligand

Abstract

Although there is evidence for distinct roles of myeloid dendritic cells (DCs [mDCs]) and plasmacytoid pre-DCs (pDCs) in regulating T cell–mediated adaptive immunity, the concept of functional DC subsets has been questioned because of the lack of a molecular mechanism to explain these differences. In this study, we provide direct evidence that maturing mDCs and pDCs express different sets of molecules for T cell priming. Although both maturing mDCs and pDCs upregulate the expression of CD80 and CD86, only pDCs upregulate the expression of inducible costimulator ligand (ICOS-L) and maintain high expression levels upon differentiation into mature DCs. High ICOS-L expression endows maturing pDCs with the ability to induce the differentiation of naive CD4 T cells to produce interleukin-10 (IL-10) but not the T helper (Th)2 cytokines IL-4, -5, and -13. These IL-10–producing T cells are T regulatory cells, and their generation by ICOS-L is independent of pDC-driven Th1 and Th2 differentiation, although, in the later condition, some contribution from endogenous IL-4 cannot be completely ruled out. Thus, in contrast to mDCs, pDCs are poised to express ICOS-L upon maturation, which leads to the generation of IL-10–producing T regulatory cells. Our findings demonstrate that mDC and pDCs are intrinsically different in the expression of costimulatory molecules that drive distinct types of T cell responses.

On watching the watchers: IDO and type I/II IFN

“…Whatever the mechanisms involved in the control of IFN-a by IDO, which is in turn controlled by the former, the present observations by Manlapat et al [20], combined with the previous data on the role of pDC and IFN in the balance of inflammation and tolerance [4,5,9,10,21], call attention to the importance of the IDO-dependent effects of B7 ligands, including CTLA-4-Ig [11], as therapeutic agents. At the same time, these studies further establish IDO as a truly immunoregulatory enzyme.…”

“…In most of these models, the protective function of pDC and the associated type I IFN response appears to be an intrinsic ability of the system to co-activate cytostatic mechanisms, induce the death of effector Th2 cells, or polarize T cells towards an IL-10-producing Treg phenotype [3,4,10,13].…”

“…Maturing pDC have an intrinsic ability to inhibit immune responses by inducing IL-10-producing T regulatory (Treg) cells. These Treg cells are capable of preventing excessive inflammation, which would damage the host, during infection [10].…”

Peripheral virus-specific T-cell interleukin-10 responses develop early in acute hepatitis C infection and become dominant in chronic hepatitis

“…This suggested that HCV-specific T-cells are maintained at similar frequency, scope and antigenic hierarchy in chronic HCV infection as those in recovered HCV infection but are polarized toward IL-10 production rather than the IFNγ production characteristic of spontaneous HCV clearance. Possible explanations for this finding include altered T-cell maturation due to virus-induced dysfunction of antigen-presenting cells (29,50,51), viral epitope mutation (52), or altered T-cells costimulation (53)(54)(55). In the chronic phase, peripheral HCV-specific Tr1 response did not correlate with CD4 + CD25 + regulatory T-cell frequency, distinguishing Tr1 cells from CD4 + CD25 + Tregs (26,27).…”

Origin and functional specializations of DC subsets in the lung

“…The mechanisms behind this specific form of inhalation tolerance are less clear. In vitro and in vivo studies have clearly shown that pDC stimulate the formation of Treg, possibly in an inducible costimulatory ligand-1(ICOSL)-dependent manner [9,63]. The function of pDC is also tightly controlled.…”