In vivo CD8+ T cell dynamics in the liver of Plasmodium yoelii immunized and infected mice

• Published in: PloS one Vol. 8; no. 8; p. e70842
• Main Authors: Cabrera, Mynthia, Pewe, Lecia L, Harty, John T, Frevert, Ute
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.08.2013; Public Library of Science (PLoS)
• Subjects: Adoptive Transfer; Animals; Antigens; Attenuation; Biocompatibility; Biology; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cytokines; Cytotoxicity; Dendritic cells; Effector cells; Health aspects; Health problems; Hepatocytes; Hepatocytes - immunology; Hepatocytes - parasitology; Immunity; Immunization; Liver; Liver - immunology; Liver - parasitology; Lymphocytes; Lymphocytes T; Malaria; Malaria - immunology; Malaria - prevention & control; Malaria vaccines; Medicine; Mice; Mice, Inbred BALB C; Microscopy; Microvasculature; Parasites; Parasitic diseases; Parasitology; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii - physiology; Rodents; Spleen; Sporozoites; Sporozoites - physiology; T cells; Toxicity; Tropical diseases; Vaccination; Vaccines; Vector-borne diseases; New York; United States > US; Iowa City Iowa
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0070842

Plasmodium falciparum malaria remains one of the most serious health problems globally and a protective malaria vaccine is desperately needed. Vaccination with attenuated parasites elicits multiple cellular effector mechanisms that lead to Plasmodium liver stage elimination. While granule-mediated cytotoxicity requires contact between CD8+ effector T cells and infected hepatocytes, cytokine secretion should allow parasite killing over longer distances. To better understand the mechanism of parasite elimination in vivo, we monitored the dynamics of CD8+ T cells in the livers of naïve, immunized and sporozoite-infected mice by intravital microscopy. We found that immunization of BALB/c mice with attenuated P. yoelii 17XNL sporozoites significantly increases the velocity of CD8+ T cells patrolling the hepatic microvasculature from 2.69±0.34 μm/min in naïve mice to 5.74±0.66 μm/min, 9.26±0.92 μm/min, and 7.11±0.73 μm/min in mice immunized with irradiated, early genetically attenuated (Pyuis4-deficient), and late genetically attenuated (Pyfabb/f-deficient) parasites, respectively. Sporozoite infection of immunized mice revealed a 97% and 63% reduction in liver stage density and volume, respectively, compared to naïve controls. To examine cellular mechanisms of immunity in situ, naïve mice were passively immunized with hepatic or splenic CD8+ T cells. Unexpectedly, adoptive transfer rendered the motile CD8+ T cells from immunized mice immotile in the liver of P. yoelii infected mice. Similarly, when mice were simultaneously inoculated with viable sporozoites and CD8+ T cells, velocities 18 h later were also significantly reduced to 0.68±0.10 μm/min, 1.53±0.22 μm/min, and 1.06±0.26 μm/min for CD8+ T cells from mice immunized with irradiated wild type sporozoites, Pyfabb/f-deficient parasites, and P. yoelii CS280-288 peptide, respectively. Because immobilized CD8+ T cells are unable to make contact with infected hepatocytes, soluble mediators could potentially play a key role in parasite elimination under these experimental conditions.