CD47-mediated selective accumulation of mature Ly49h+ NK cells to the brain associates with the pathogenesis of cerebral malaria in mice.

CD47 is an antiphagocytic ("don't eat me") signal expressed on all cells that inhibits programmed cell removal of self, and loss of this molecule by aging erythrocytes is associated with increased susceptibility to clearance by macrophages. Previously, we have demonstrated that absence of CD47 confers resistance to infection with nonlethal murine malaria Plasmodium yoelii 17XNL. Furthermore, CD47 blockade with an anti-CD47 monoclonal antibody promotes survival and reduces pathologic features of experimental cerebral malaria (ECM) during infection with lethal murine malaria P. berghei ANKA (Pb-A). To further define the immunological basis of CD47 regulation of ECM, we compared Pb-A infection in wild-type (WT) versus CD47 genetic knockout (CD47-/-) mice on the C57BL/6 background. Absence of CD47 resulted in partial but significant (log-rank P < 0.001) resistance to ECM and was associated with diminished sequestration of natural killer (NK) cells, CD4+ T cells, and CD8+ T cells (immune cell subsets essential for ECM pathogenesis) within the brain and lower levels of circulating interleukin-10 and MIP1β cytokines. Most importantly, our data show a critical role for CD47 in the maturation, activation, and recruitment of brain-sequestered NK cells. In mice experiencing ECM, CD47 associates with the exclusive expression of Ly49h (an activation receptor that elicits IFN-γ and cytolytic activity upon stimulation) by a subset of brain-sequestered CD11b+CD49b+ NK cells. Our studies provide insights on a previously undefined role of CD47 in NK cell-mediated pathogenesis of ECM and an increased understanding of the role of CD47 in NK cell biology.