Instructive cytokine signals in dendritic cell lineage commitment

Abstract

Clarifying the signals that lead to dendritic cell (DC) development and identifying cellular intermediates on their way to DC differentiation are essential steps to understand the dynamic regulation of number, localization, and functionality of these cells. In the past decade, much knowledge on cytokines, transcription factors, and successive progenitors involved in steady-state and demand-adapted DC development was gained. From the stage of multipotent progenitors, DCs are generated from Flt3(+) intermediates, irrespective of lymphoid or myeloid commitment, making fms-related tyrosine kinase 3 ligand one of the major regulators for DC development. Additional key cytokines involved are granulocyte-macrophage colony-stimulating factor (GM-CSF) and M-CSF, with each being essential for particular DC subsets and leading to specific activation of downstream transcription factors. In this review, we seek to draw an integrative view on how instructive cytokine signals acting on intermediate progenitors might lead to the generation of specific DC subsets in steady-state and during inflammation. We hypothesize that the lineage potential of a progenitor might be determined by the set of cytokine receptors expressed that make it responsive to further receive lineage instructive signals. Commitment to a certain lineage might consequently occur when lineage-relevant cytokine receptors are further upregulated and others for alternative lineages are lost. Along this line, we emphasize the role that diverse microenvironments have in influencing the generation of DC subsets with specific functions throughout the body.

C/EBPα is required for development of dendritic cell progenitors

“…The differentiation of DCs is controlled by the expression of growth factor receptors that together with transcription factors direct cell fates. 39,40 We wanted to test whether C/EBPa was responsible for the induction of well-characterized DC-related transcription factors, so we analyzed the expression patterns of these factors and the interaction of C/EBPa with their promoters, or up-and downstream regulatory elements. To do this, sorted CMPs were used to For personal use only.…”

Organ-Specific Cellular Requirements for In Vivo Dendritic Cell Generation

“…Different key growth factors for DC development have been identified (26). DC differentiation in lymphoid organs is mostly driven by Flt3 ligand (Flt3-L) (16,(27)(28)(29) with little contribution by other cytokines (30).…”

Antiviral Regulation in Porcine Monocytic Cells at Different Activation States

“…A similar paradigm has been postulated for DCs, with type I DCs representing a subset inducing Th1 responses and type II DCs activating Th2 responses (8,9). Nonetheless, the criteria for DC polarization and associated activation markers remain elusive in all species (1,6,7). Monocytic cells at different activation statuses, as well characterized in Ms, functionally exert phenotypes to regulate inflam-mation, tissue repair, T-and B-cell proliferation, phagocytosis, and antimicrobial activity against bacteria and helminths (3)(4)(5).…”

“…A question we confronted for molecular vaccine design, however, is how can sufficient PRRSV replication activity be achieved when expressing an IFN with high PRRSV antiviral activity? To address this problem, we inserted a leader linker in front of the IFN coding region that encodes a six-histidine tag, (His) 6 , plus a 10-residue polypeptide containing a C-terminal cleavage peptide (GKPILFFRLK) of cathepsin D (CSTD), a protease induced during PRRSV infection in Ms (Y. Sang, unpublished data).…”

“…Accordingly, the other subclasses of M2 cells include M2b, obtained by triggering of Fc␥ receptors plus the stimulation of Toll-like receptors (TLRs) in Ms, and M2c of deactivation programs elicited by immunosuppressive cytokines and hormones, such as IL-10, glucocorticoids (GCs), and transforming growth factor ␤ (TGF-␤) (2-4). Despite not being well studied, the M1/M2 activation paradigm is represented in both monocytes and DCs (1,(5)(6)(7). For example, human monocytes are divided based on the expression of CD16, with CD16 ϩ monocytes representing M1 cells, which are more proinflammatory and microbicidal (5).…”