Interferon-producing killer dendritic cells (IKDCs) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors

Abstract

Interferon-producing killer dendritic cells (IKDCs) have only recently been described and they share some properties with plasmacytoid dendritic cells (pDCs). We now show that they can arise from some of the same progenitors. However, IKDCs expressed little or no RAG-1, Spi-B, or TLR9, but responded to the TLR9 agonist CpG ODN by production of IFN␥. The RAG-1 ؊ pDC2 subset was more similar to IKDCs than RAG-1 ؉ pDC1s with respect to IFN␥ production. The Id-2 transcriptional inhibitor was essential for production of IKDCs and natural killer (NK) cells, but not pDCs. IKDCs developed from lymphoid progenitors in culture but, unlike pDCs, were not affected by Notch receptor ligation. While IKDCs could be made from estrogen-sensitive progenitors, they may have a slow turnover because their numbers did not rapidly decline in hormonetreated mice. Four categories of progenitors were compared for IKDC-producing ability in transplantation assays. Of these, Lin ؊ Sca- IntroductionFunctionally specialized cells in the innate and adaptive immune systems are still being discovered, 1-3 and each needs to be fully understood in terms of developmental history. Replacement of immune effector cells from hematopoietic stem cells (HSCs) is an ordered process where multiple lineage potentials are gradually lost coincident with gain of specialized functions, and within the context of patterns of transcriptional activity and surface marker expression. [4][5][6][7][8][9] The focus of the present study was on recently identified interferon-producing killer dendritic cells (IKDCs). IKDCs exhibit "hybrid" phenotypic and functional characteristics of dendritic and natural killer (NK) cells. 2,3 Shared properties include expression of B220, CD11c, CD122, and NK1.1, as well as production of interferons, capability of antigen presentation, and strong cytotoxic or antitumor activities. Thus, IKDCs are unique, multifunctional cells that merit study with respect to development.HSCs and several categories of primitive progenitors reside in the lineage marker-negative Sca1 ϩ c-kit hi (LSK) fraction of BM. Up-regulation of Flk-2 and corresponding loss of erythroid/ megakaryocytic potential is an early event that sets the stage for lymphopoiesis. 10,11 LSKs include 2 overlapping subsets of lymphopoietic cells identified as Flk-2 ϩ/Ϫ Thy1.1 Ϫ L-selectin ϩ progenitors (LSPs) and RAG-1 ϩ Flk-2 ϩ CD27 ϩ early lymphoid progenitors (ELPs). [12][13][14] Although clearly B-and T-lymphoid specified, LSPs and ELPs retain some potential for myeloid, NK, and dendritic cell (DC) lineages. Firm commitment in these pathways and repression of alternative fates involve expression of key transcription factors, such as Pax5, Notch-1, and Spi-B, as well as environmental cues. 15 All lymphoid progenitors in BM are rapidly and preferentially depleted in estrogen-treated mice. 16,17 Progenitors that can more quickly give rise to lymphocytes reside in a Lin Ϫ Flk-2 ϩ c-Kit Lo prolymphocyte (Pro-L) fraction that includes Lin Ϫ c-Kit Lo Sca-1 ϩ IL-7R␣ ϩ common lymphoid proge...

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

“…There is evidence that these so-called NKDCs (that comprise the IKDC subset) play an important role in the defense against Listeria primarily by producing IFN-g in response to IL-12 and IL-18. 4 Recently published experiments show that NK and IKDC cell lineages originate in mice from different primitive lymphoid precursors, supporting the notion that these cells represent a distinct hematopoietic lineage, 5 albeit an homologous cell subset in human beings still defies identification. 6,7 However, several groups have recently questioned the existence of this cell subset as a separate lineage from NK cells, with the putative antigen presentation function of IKDC at the core of the controversy.…”

Bone Marrow-Derived IFN-Producing Killer Dendritic Cells Account for the Tumoricidal Activity of Unpulsed Dendritic Cells

“…However, some controversy has arisen regarding the identity and function of the IKDC population, which shares the same phenotype as the CD11c int B220 ϩ NK1.1 ϩ CD49 ϩ population described in this study (23)(24)(25)28). We have elected to call these cells BM-IKDC but stress that our data, as far as they go, do not exclude the possibility that the BM-IKDC may represent activated and highly potent NK cells capable of inducing regression of established tumor through induction of secondary immune responses, but without having Ag presentation capacity in their own right.…”

Les IKDC

“…Les IKDC sont apparentées aux lymphocytes NK conventionnels (car elles expriment CD122, NKG2D, NKp46 [17][18][19] et dépendent du facteur de transcription Id2 [20], de l'IL-15 et de son récepteur IL-15Rα pour leur ontogénie [21]) mais ont une origine de différenciation unique à partir d'un progéniteur lymphoïde c-kit fort CD62L + [22]. De plus, d'un point de vue fonctionnel, les IKDC se distinguent des NK convention- …”