T-cell immunity to peptide epitopes of liver-stage antigen 1 in an area of Papua New Guinea in which malaria is holoendemic

Abstract

Liver-stage antigen 1 (LSA1) is one of several pre-erythrocytic antigens considered for inclusion in a multiantigen, multistage subunit vaccine against falciparum malaria. We examined T-cell proliferation and cytokine responses to peptides corresponding to amino acids 84 to 107, 1813 to 1835, and 1888 to 1909 of LSA1 in asymptomatic adults living in an area of Papua New Guinea where malaria is holoendemic. Whereas T cells from North Americans never exposed to malaria did not respond to any of the peptides, those from 52 of 55 adults from the area where malaria is endemic had vigorous proliferation responses to one or more of the LSA1 peptides (mean stimulation indices of 6.8 to 7.2). Gamma interferon (IFN-␥) production driven by LSA1 peptides ranged from 34 to more than 3,500 pg/2 ؋ 10 6 cells, was derived primarily from CD8 ؉ cells, and was dissociated from T-cell proliferation. The frequencies of IFN-␥ response to the amino acid 1819 to 1835 and 1888 to 1909 peptides were significantly greater than that to the amino acid 84 to 107 peptide (87 and 88% versus 33% of subjects; P < 0.0001). In contrast to proliferation and IFN-␥, interleukin 4 (IL-4) and/or IL-5 responses to LSA1 peptides were detected in only 18% of the subjects. These data show that T-cell immunity to epitopes in the N-and C-terminal regions of LSA1 are common in persons living in this area of Papua New Guinea where malaria is endemic. The dominance of type 1 CD8 cell IFN-␥ responses is consistent with a role for this T-cell population in immunity to liver-stage Plasmodium falciparum in humans.

Effector and memory CD8+ T cells as seen in immunity to malaria

“…Immunization of mice with HEP17 plasmid DNA induced CD8 þ T cells against a yet to be identified epitope in the protein (36). Further studies on TRAP/SSP2 and HEP17/ EXP1 have been severely hampered by the failure to identify putative epitopes recognized by protective CD8 þ T cells (37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”

Influence of age and HLA type on interferon-gamma (IFN-γ) responses to a naturally occurring polymorphic epitope ofPlasmodium falciparumliver stage antigen-1 (LSA-1)

“…Recent studies conducted in Kenya and Gabon indicate that cytokine responses to N-and C-terminal non-repeat regions of LSA-1 correlate with partial resistance to re-infection [13±15]. Using a consensus sequence based on the NF54 P. falciparum isolate, we previously characterized T cell cytokine responses to peptides encoded by LSA-1 amino acid residues 84±107, 1813±1835, and 1888±1909 in adults living in the Wosera area of East Sepik Province, Papua New Guinea [16]. Whereas only 18% of individuals had IL-4 or IL-5 responses, IFN-g production stimulated by the N-terminal 84±107 peptide was observed in 33% of the subjects.…”

Interleukin-10 Responses to Liver-Stage Antigen 1 Predict Human Resistance toPlasmodium falciparum

“…Human studies have identified low levels of CTL activity in naturally exposed populations (1,10,16,22) and in irradiated sporozoite-immunized volunteers (24,33). Other studies indicate that antibody, proliferative, cytokine, and CTL responses to LSA-1 peptides are detectable in naturally exposed individuals (8,11,12). Connelly et al reported that in an area of Papua New Guinea where malaria is holoendemic, 10 of 11 individuals with two negative blood smears (obtained 6 months apart) produced detectable IFN-␥ in response to an LSA-1 peptide, while only 9 of 27 individuals with one or two positive blood smears produced detectable IFN-␥ in response to this peptide (8).…”

“…Other studies indicate that antibody, proliferative, cytokine, and CTL responses to LSA-1 peptides are detectable in naturally exposed individuals (8,11,12). Connelly et al reported that in an area of Papua New Guinea where malaria is holoendemic, 10 of 11 individuals with two negative blood smears (obtained 6 months apart) produced detectable IFN-␥ in response to an LSA-1 peptide, while only 9 of 27 individuals with one or two positive blood smears produced detectable IFN-␥ in response to this peptide (8). No association was found between blood smear status and IFN-␥ responses to two other LSA-1 peptides.…”