Plasmacytoid DCs fail to soar without Ikaros

Comment on Allman et al, page 4025

The developmental pathway of plasmacytoid DCs (pDCs) is poorly understood. In this issue of Blood, Allman and colleagues break new ground by demonstrating that the transcription factor Ikaros is crucial for terminal differentiation of pDCs.

Plasmacytoid dendritic cells (pDCs) specialize in secreting high amounts of type I interferons (IFNα and IFNβ) in response to DNA and RNA viruses. Because they share some attributes of conventional DCs (cDCs), particularly MHC class II expression, pDCs are also considered a DC subset capable of antigen presentation. Thus, pDCs are thought to be crucial for initiating antiviral innate responses as well as jump-starting adaptive responses.

Although pDCs were identified some time ago, their origin, development, and lineage relationship with other cells of the immune system remain only partially defined. It has been clearly established that Flt-3 ligand (Flt-3L) directs the development of pDCs from hematopoietic stem cells (HSCs) in the bone marrow.¹  However, whether pDCs develop as a branch of the lymphoid or myeloid lineage is unclear, as pDCs have been reported to differentiate from the common lymphoid progenitor, the common myeloid progenitor, or both. These observations led to the suggestion that pDC development is more flexible than that of classical myeloid and lymphoid cells.

Strong evidence for developmental plasticity has been provided by studies aimed at defining the transcriptional program driving the development of pDCs from HSCs; collectively, this work has identified multiple transcription factors previously implicated in either lymphoid or myeloid development. The transcription factor Spi-B promotes pDC and B-cell development over that of T cells,¹  whereas IFN regulatory factor 8 (IRF-8; also called ICSBP), a critical transcriptional factor for the myeloid cell lineage, is required for the development of both pDCs and CD8α⁺cDCs.^2,3  pDC development is negatively regulated by members of the basic helix-loop helix (bHLH) family, which also block development of B and T cells, sparing the development of cDCs and natural killer (NK) cells.¹ 

The transcription factor Ikaros is required for the development of multiple hematopoietic lineages⁴  and has also been implicated in pDC development. Among various Ikaros mutant mice that have been generated, a null mutation prevented development of the CD8α^– cDC subset, while a dominant-negative mutation resulted in lack of both CD8α⁺ and CD8α^– cDCs.⁵  In the present study, Allman and colleagues analyzed a mutant mouse line (Ik^L/L) expressing a truncated Ikaros protein that functions normally but is expressed at very low levels. Allman et al showed that Ik^L/L mice lack peripheral pDCs, but not cDCs. Remarkably, Ik^L/L bone marrow does contain a pDC population that appears to be blocked at an early stage of differentiation characterized by low levels of B220 and lack of the cell surface receptor Ly-49Q. Moreover, Ik^L/L bone marrow cells respond to Flt-3L in vitro by generating immature pDCs.

These results demonstrate that the transcriptional program induced by Flt-3L–Flt-3 signaling is necessary but not sufficient for pDC development. Optimal amounts of Ikaros are also required for terminal differentiation of pDCs. In contrast, suboptimal Ikaros is sufficient for development of cDCs, possibly due to concomitant expression of Aiolos (Ikaros-related transcription factor). Thus, the study by Allman et al defines, for the first time, an intermediate stage in the development of pDCs and unveils an unexpected role for Ikaros in promoting pDC differentiation beyond this step. In light of this study, pDC development appears to be exclusive, as it requires a unique combination of transcription factors that are shared with other lineages. While certain conditions that favor this combination will promote pDC development, any milieu that does not will effectively shift development toward other cell types. This exquisite control of pDC development may be beneficial for mounting both innate and adaptive immune responses against viruses.

The author declares no competing financial interests. ▪