Contributions of IFN-γ and granulysin to the clearance of Plasmodium yoelii blood stage

• DOI: 10.1371/journal.ppat.1008840
• Publication Date: 2020-09-10T17:25:28Z
• Authors: Natália Satchiko ...; Patrick Orestes d...; Júlia Teixeira de...; Andréa Teixeira-C...; Judy Lieberman; Caroline Junqueira; Ricardo Tostes Ga...
• Keywords: Antigens, Differentiation, T-Lymphocyte; Erythroblasts; QH301-705.5; T cells; Cytotoxic T cells; CD8-Positive T-Lymphocytes; Parasitemia; Interferon-gamma; Mice; 03 medical and health sciences; 0302 clinical medicine; Pathogenic Microbiology; Enzymes and Coenzymes; Animals; Amino Acids; Biology (General); Hemic and Immune Systems; Mice, Knockout; Mice, Inbred BALB C; and Proteins; Plasmodium yoelii; RC581-607; Parasitic diseases; Malaria; 3. Good health; Blood; Immunology of Infectious Disease; Parasitology; Immunologic diseases. Allergy; Peptides; Spleen; Research Article

P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8+ T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics. Infection with P. yoelii caused extramedullary erythropoiesis, reticulocytosis and expansion of CD8+CD44+CD62L- IFN-γ-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic is dependent on IFN-γ-induced transcription of IRF-1, MHC-I and β2-microglobulin (β2-m) in erythroblasts. Consistently, CTLs from infected wild type (WT) mice formed immune synapses with iRetics in an IFN-γ- and MHC-I-dependent manner. When challenged with P. yoelii 17XNL, WT mice cleared parasitemia and survived, while IFN-γ KO mice remained parasitemic and all died. β2-m KO mice that do not express MHC-I and have virtually no CD8+ T cells had prolonged parasitemia, and 80% survived. Because mice do not express GNLY, GNLY-transgenic mice can be used to assess the in vivo importance of GNLY. Parasite clearance was accelerated in GNLY-transgenic mice and depletion of CD8+ T cells ablated the GNLY-mediated resistance to P. yoelii. Altogether, our results indicate that in addition to previously described mechanisms, IFN-γ promotes host resistance to the Retic-tropic P. yoelii 17XNL strain by promoting MHC-I expression on iRetics that become targets for CD8+ cytotoxic T lymphocytes and GNLY.