Cytotoxic activities of CD8 + T cells collaborate with macrophages to protect against blood-stage murine malaria

The protective immunity afforded by CD8 + T cells against blood-stage malaria remains controversial because no MHC class I molecules are displayed on parasite-infected human erythrocytes. We recently reported that rodent malaria parasites infect erythroblasts that express major histocompatibility complex (MHC) class I antigens, which are recognized by CD8 + T cells. In this study, we demonstrate that the cytotoxic activity of CD8 + T cells contributes to the protection of mice against blood-stage malaria in a Fas ligand (FasL)-dependent manner. Erythroblasts infected with malarial parasites express the death receptor Fas. CD8 + T cells induce the externalization of phosphatidylserine (PS) on the infected erythroblasts in a cell-to-cell contact-dependent manner. PS enhances the engulfment of the infected erythroid cells by phagocytes. As a PS receptor, T-cell immunoglobulin-domain and mucin-domain-containing molecule 4 (Tim-4) contributes to the phagocytosis of malaria-parasite-infected cells. Our findings provide insight into the molecular mechanisms underlying the protective immunity exerted by CD8 + T cells in collaboration with phagocytes. DOI: http://dx.doi.org/10.7554/eLife.04232.001 eLife digest The immune system consists of several different types of cell that work together to prevent infection and disease. For example, immune cells called cytotoxic CD8 + T cells kill tumor cells or other cells that are infected. To do so, the CD8 + T cells must recognize certain molecules on the surface of the tumor or infected cells and bind to them. Malaria is an infectious disease caused by the Plasmodium parasite, which is transferred between individuals by mosquitoes. The parasite is able to evade the immune system—so much so that it is not well understood how the immune system tries to respond to stop the infection. This has made it difficult to develop a vaccine that protects against malaria. During the latter stages of a malaria infection, the parasite infects the host’s red blood cells. It was long believed that CD8 + T cells did not help to eliminate the red blood cells that had been infected by Plasmodium . However, recent work in mice suggested that CD8 + T cells do respond to infected erythroblasts—precursor cells that develop into red blood cells—and that CD8 + T cells help protect mice against blood-stage malaria. Now, Imai et al. describe how the CD8 + T cells in mice help to kill erythroblasts infected with Plasmodium yoelli , a species of the parasite used to study malaria in mice. The infected cells display a protein called Fas on their surface. Imai et al. found that, during a malaria infection, the CD8 + T cells produce a protein that can interact with Fas. This interaction causes the infected cell to move a signaling molecule to its outside surface, which encourages another type of immune cell to engulf and destroy the infected cell. This knowledge of how CD8 + T cells fight Plasmodium parasites in the bloodstream could now help to develop new types of blood-stage vaccine for malaria. DOI: http://dx.doi.org/10.7554/eLife.04232.002