Regulation by SIRPα of dendritic cell homeostasis in lymphoid tissues

Abstract

The 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 CD11c(high) 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.

Inhibition of SIRPα in dendritic cells potentiates potent antitumor immunity

“…The number of CD11c C DCs was reduced in secondary lymphoid tissues of mice expressing a mutant form of SIRPa that lacks the cytoplasmic region. 29 It is of note that this mutant SIRPa is structurally similar to SIRPg, another member of the SIRP family which is functionally involved in T-cell proliferation and activation. 30 As the mutant SIRPa is still able to ligate CD47 on T cells, it is not yet known if this mutant can represent a functionally deficient SIRPa in DCs.…”

Dendritic Cell-Specific Ablation of the Protein Tyrosine Phosphatase Shp1 Promotes Th1 Cell Differentiation and Induces Autoimmunity

“…For analysis or preparation of DCs or F4/80 + macrophages from the spleen, peripheral LNs, or thymus (26,27), tissue was minced with the use of forceps and then digested with collagenase (Wako, Osaka, Japan) at 400 U/ml in the presence of 5 mM EDTA (Sigma) for 30 min at 37˚C. The undigested fibrous material was removed by filtration through a 70-mm cell strainer (BD Falcon, San Jose, CA), and RBCs in the filtrate were lysed with Gey's solution.…”

Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

“…SIRPα is especially abundant in myeloid cells such as macrophages and DCs, whereas it is expressed at only low levels in T, B, NK, and NKT cells (10)(11)(12)(13). The extracellular region of SIRPα interacts with its ligand CD47, which is expressed in most cell types (14) and is also a member of the Ig superfamily (8,9,14).…”