Defining rules of CD8(+) T cell expansion against pre-erythrocytic Plasmodium antigens in sporozoite-immunized mice

• Published in: Malaria journal Vol. 15; no. 236; p. 238
• Main Authors: Billman, Zachary P, Kas, Arnold, Stone, Brad C, Murphy, Sean C
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26-04-2016; BioMed Central
• Subjects: Animals; Antibodies; Antigens; Care and treatment; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - parasitology; Dosage and administration; Enzyme-Linked Immunosorbent Assay; Epitopes - immunology; Female; Malaria; Malaria Vaccines - immunology; Mice; Mice, Inbred C57BL; Plasmodium berghei - immunology; Plasmodium yoelii - immunology; Protozoan Proteins - immunology; Protozoan Proteins - metabolism; Sequence Analysis, DNA; Sporozoites - immunology; T cells; Viral antibodies; CD8 T cell; Plasmodium; Malaria; RAS; Cross-species; GAP; Late-arresting; Heterologous; Secondary expansion
• ISSN: 1475-2875; 1475-2875
• DOI: 10.1186/s12936-016-1295-5

Whole Plasmodium sporozoites serve as both experimental tools and potentially as deployable vaccines in the fight against malaria infection. Live sporozoites infect hepatocytes and induce a diverse repertoire of CD8(+) T cell responses, some of which are capable of killing Plasmodium-infected hepatocytes. Previous studies in Plasmodium yoelii-immunized BALB/c mice showed that some CD8(+) T cell responses expanded with repeated parasite exposure, whereas other responses did not.
Here, similar outcomes were observed using known Plasmodium berghei epitopes in C57BL/6 mice. With the exception of the response to PbTRAP, IFNγ-producing T cell responses to most studied antigens, such as PbGAP50, failed to re-expand in mice immunized with two doses of irradiated P. berghei sporozoites. In an effort to boost secondary CD8(+) T cell responses, heterologous cross-species immunizations were performed. Alignment of P. yoelii 17XNL and P. berghei ANKA proteins revealed that >60 % of the amino acids in syntenic orthologous proteins are continuously homologous in fragments ≥8-amino acids long, suggesting that cross-species immunization could potentially trigger responses to a large number of common Class I epitopes. Heterologous immunization resulted in a larger liver burden than homologous immunization. Amongst seven tested antigen-specific responses, only CSP- and TRAP-specific CD8(+) T cell responses were expanded by secondary homologous sporozoite immunization and only those to the L3 ribosomal protein and S20 could be re-expanded by heterologous immunization. In general, heterologous late-arresting, genetically attenuated sporozoites were better at secondarily expanding L3-specific responses than were irradiated sporozoites. GAP50 and several other antigens shared between P. berghei and P. yoelii induced a large number of IFNγ-positive T cells during primary immunization, yet these responses could not be re-expanded by either homologous or heterologous secondary immunization.
These studies highlight how responses to different sporozoite antigens can markedly differ in recall following repeated sporozoite vaccinations. Cross-species immunization broadens the secondary response to sporozoites and may represent a novel strategy for candidate antigen discovery.