Regulation by SIRPα of dendritic cell homeostasis in lymphoid tissues

The molecular basis for regulation of dendritic cell (DC) development and homeostasis remains unclear. Signal regulatory protein alpha (SIRP alpha), 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 SIRP alpha that lacks the cytoplasmic region. We also found that SIRP alpha is required intrinsically within cDCs or DC precursors for the homeostasis of splenic CD4(+) cDCs. Differentiation of bone marrow cells from SIRP alpha 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 SIRP alpha 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. SIRP alpha as well as its ligand, CD47, are thus important for the homeostasis of CD4(+) cDCs or double negative cDCs in lymphoid tissues. (Blood. 2010;116(18):3517-3525)