Abstract
AbstractThe molecular basis for regulation of dendritic cell (DC) development and homeostasis remains unclear. Signal regulatory protein α (SIRPα), an immunoglobulin superfamily protein that is predominantly expressed in DCs, mediates cell-cell signaling by interacting with CD47, another immunoglobulin superfamily protein. We now show that the number of CD11chigh DCs (conventional DCs, or cDCs), in particular, that of CD8−CD4+ (CD4+) cDCs, is selectively reduced in secondary lymphoid tissues of mice expressing a mutant form of SIRPα that lacks the cytoplasmic region. We also found that SIRPα is required intrinsically within cDCs or DC precursors for the homeostasis of splenic CD4+ cDCs. Differentiation of bone marrow cells from SIRPα mutant mice into DCs induced by either macrophage-granulocyte colony-stimulating factor or Flt3 ligand in vitro was not impaired. Although the accumulation of the immediate precursors of cDCs in the spleen was also not impaired, the half-life of newly generated splenic CD4+ cDCs was markedly reduced in SIRPα mutant mice. Both hematopoietic and nonhematopoietic CD47 was found to be required for the homeostasis of CD4+ cDCs and CD8−CD4−(double negative) cDCs in the spleen. SIRPα as well as its ligand, CD47, are thus important for the homeostasis of CD4+ cDCs or double negative cDCs in lymphoid tissues.
Highlights
Dendritic cells (DCs) are professional antigen-presenting cells that play 2 major roles in the immune system: initiation and modulation of the immune responses of T cells to exogenous pathogens, and maintenance of T-cell tolerance to self-components.[1]
To clarify the role of SIRP␣ in the regulation of CD8Ϫ conventional DCs (cDCs), we investigated the size of cDC subpopulations in the spleen of SIRP␣ mutant (MT) mice that express a form of SIRP␣ lacking most of the cytoplasmic region.[23,26]
With the use of flow cytometric analysis, we found that the proportion as well as the absolute number of cDCs in the spleen of SIRP␣ MT mice were markedly decreased compared with those in WT mice, whereas the proportion and number of plasmacytoid DCs (pDCs) in the spleen were similar for WT and SIRP␣ MT mice (Figure 1A)
Summary
Dendritic cells (DCs) are professional antigen-presenting cells that play 2 major roles in the immune system: initiation and modulation of the immune responses of T cells to exogenous pathogens, and maintenance of T-cell tolerance to self-components.[1] The mouse spleen harbors 2 major subtypes of DCs, namely, CD11chigh conventional DCs (cDCs) and plasmacytoid DCs (pDCs), defined as CD11cint B220ϩ cells The latter DCs produce type I interferons in response to viral and bacterial pathogens.[1,2] The cDCs are further classified into CD4ϩCD8Ϫ cDCs (CD4ϩ cDCs), CD4ϪCD8Ϫ cDCs (double negative [DN] cDCs), and CD4ϪCD8ϩ cDCs (CD8ϩ cDCs).[3,4] CD8Ϫ cDCs are present predominantly in the marginal zone of splenic lymphoid follicles as well as in marginal zone– bridging regions, whereas CD8ϩ cDCs are enriched in the periarteriolar lymphoid sheaths, which are populated largely by T cells, in the white pulp of the spleen.[5] These cDC subtypes are in dynamic balance. The immediate precursors of cDCs, defined as lineage-negative CD11cϩ MHC class IIϪ SIRP␣int Flt3ϩ cells (pre-cDCs),[7,8,9] are widely distributed in bone marrow (BM) as well as in secondary lymphoid tissues and circulating blood, and they are thought to maintain cDCs in lymphoid tissues under steady-state conditions
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