Abstract
Human leishmaniasis is a public health problem worldwide for which the development of a vaccine remains a challenge. T cell-mediated immune responses are crucial for protection. Peptide vaccines based on the identification of immunodominant T cell epitopes able to induce T cell specific immune responses constitute a promising strategy. Here, we report the identification of human leukocyte antigen class-I (HLA-I) and -II (HLA-II)-restricted multi-epitope peptides from Leishmania proteins that we have previously described as vaccine candidates. Promastigote Surface Antigen (PSA), LmlRAB (L. major large RAB GTPase) and Histone (H2B) were screened, in silico, for T cell epitopes. 6 HLA-I and 5 HLA-II-restricted multi-epitope peptides, able to bind to the most frequent HLA molecules, were designed and used as pools to stimulate PBMCs from individuals with healed cutaneous leishmaniasis. IFN-γ, IL-10, TNF-α and granzyme B (GrB) production was evaluated by ELISA/CBA. The frequency of IFN-γ-producing T cells was quantified by ELISpot. T cells secreting cytokines and memory T cells were analyzed by flow cytometry. 16 of 25 peptide pools containing HLA-I, HLA-II or HLA-I and -II peptides were able to induce specific and significant IFN-γ levels. No IL-10 was detected. 6 peptide pools were selected among those inducing the highest IFN-γ levels for further characterization. 3/6 pools were able to induce a significant increase of the percentages of CD4+IFN-γ+, CD8+IFN-γ+ and CD4+GrB+ T cells. The same pools also induced a significant increase of the percentages of bifunctional IFN-γ+/TNF-α+CD4+ and/or central memory T cells. We identified highly promiscuous HLA-I and -II restricted epitope combinations from H2B, PSA and LmlRAB proteins that stimulate both CD4+ and CD8+ T cell responses in recovered individuals. These multi-epitope peptides could be used as potential components of a polytope vaccine for human leishmaniasis.
Highlights
Leishmaniasis is caused by an intracellular parasite of the Leishmania genus
We identified multi-epitope peptides composed of human leukocyte antigen class-I (HLA-I) and -II-restricted epitopes, using immunoinformatic tools, within Leishmania proteins previously described as potential vaccine candidates
We showed that multi-epitope peptides used as pools were able to activate IFN-γ producing CD4+ as well as CD8+ T cells, both required for parasite elimination
Summary
Leishmaniasis is caused by an intracellular parasite of the Leishmania genus It is a severely neglected tropical disease associated with considerable morbidity and mortality throughout the world. This disease transmitted by sand fly bites can have a wide spectrum of clinical manifestations ranging from self-healing cutaneous lesions to fatal visceral disease, depending on the infecting parasite species, the host immune response and the sand fly saliva components [1, 2]. Th1 CD4+ T cells producing IFN-γ and TNF-α and positive delayed type hypersensitivity (DTH) responses, have been associated with the healing process [10,11,12,13,14]. These cells have been involved in pathogenesis, trough Granzyme B (GrB) production [27,28,29,30], while other studies showed that an increase of GrB activity was associated with a good prognosis in patients with CL [31,32,33]
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