Design of multi-epitope peptides containing HLA class-I and class-II-restricted epitopes derived from immunogenic Leishmania proteins, and evaluation of CD4+ and CD8+ T cell responses induced in cured cutaneous leishmaniasis subjects.,PLOS Neglected Tropical Diseases

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Design of multi-epitope peptides containing HLA class-I and class-II-restricted epitopes derived from immunogenic Leishmania proteins, and evaluation of CD4+ and CD8+ T cell responses induced in cured cutaneous leishmaniasis subjects.
PLOS Neglected Tropical Diseases ( IF 3.4 ) Pub Date : 2020-03-16 , DOI: 10.1371/journal.pntd.0008093
Sarra Hamrouni _{1,

2,

3} , Rachel Bras-Gonçalves ₃ , Abdelhamid Kidar ₄ , Karim Aoun ₁ , Rym Chamakh-Ayari _{1,

2} , Elodie Petitdidier ₃ , Yasmine Messaoudi _{1,

2,

3} , Julie Pagniez ₃ , Jean-Loup Lemesre ₃ , Amel Meddeb-Garnaoui ₁

Affiliation

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.

中文翻译：

包含源自免疫原性利什曼原虫蛋白的HLA I类和II类限制性表位的多表位肽的设计，以及在治愈的皮肤利什曼病患者中诱导的CD4 +和CD8 + T细胞反应的评估。

人类利什曼病是世界范围内的公共卫生问题，疫苗的开发仍然是一个挑战。T细胞介导的免疫反应对于保护至关重要。基于鉴定能够诱导T细胞特异性免疫反应的免疫显性T细胞表位的肽疫苗构成了有前途的策略。在这里，我们报告了从利什曼原虫蛋白质中鉴定出人类白细胞抗原I类（HLA-I）和-II（HLA-II）限制性多表位多肽的鉴定，我们先前将其描述为候选疫苗。在计算机上筛选了前鞭毛体表面抗原（PSA），LmlRAB（大叶雷伯氏菌大型RAB GTP酶）和组蛋白（H2B）的T细胞表位。6个HLA-I和5个HLA-II限制性多表位肽，能够与最常见的HLA分子结合，设计并用作刺激皮肤利什曼病已治愈患者的PBMC的库。通过ELISA / CBA评估IFN-γ，IL-10，TNF-α和颗粒酶B（GrB）的产生。通过ELISpot定量产生IFN-γ的T细胞的频率。通过流式细胞仪分析分泌细胞因子和记忆T细胞的T细胞。在包含HLA-1，HLA-II或HLA-1和-II肽的25个肽库中，有16个能够诱导特异性和显着的IFN-γ水平。没有检测到IL-10。从诱导最高IFN-γ水平的肽库中选择6个肽库用于进一步表征。3/6库能够诱导CD4 +IFN-γ+，CD8 +IFN-γ+和CD4 + GrB + T细胞百分比的显着增加。相同的库也诱导双功能IFN-γ+ /TNF-α+ CD4 +和/或中央记忆T细胞的百分比显着增加。我们从H2B，PSA和LmlRAB蛋白中鉴定了高度混杂的HLA-I和-II限制性表位组合，这些组合物可刺激恢复个体的CD4 +和CD8 + T细胞反应。这些多表位肽可用作人利什曼病的多表位疫苗的潜在成分。

更新日期：2020-03-19

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