Toxoplasma gondii HLA-B*0702-restricted GRA7(20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8(+) T cells producing interferon-γ and reduces parasite burden in HLA-B*0702 mice.
Toxoplasma gondii HLA-B*0702-restricted GRA7(20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8(+) T cells producing interferon-γ and reduces parasite burden in HLA-B*0702 mice.
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DOI：
10.1016/j.humimm.2011.10.006
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发表时间：
2012-01
期刊：
影响因子：
2.7
通讯作者：
McLeod, Rima
中科院分区：
文献类型：
--
作者：
Cong, Hua;Mui, Ernest J.;Witola, William H.;Sidney, John;Alexander, Jeff;Sette, Alessandro;Maewal, Ajesh;El Bissati, Kamal;Zhou, Ying;Suzuki, Yasuhiro;Lee, Daniel;Woods, Stuart;Sommerville, Caroline;Henriquez, Fiona L.;Roberts, Craig W.;McLeod, Rima
在小鼠模型中，CD8+T细胞作为细胞杀伤效应和产生干扰素-γ的能力被证明是由于识别受小鼠MHC-I类分子限制的多肽而介导对弓形虫的耐药性。然而，没有弓形虫特异的HLA-B07限制性多肽被证明对弓形虫有保护作用。最近，两个弓形虫特异性限制性T细胞表位GRA720-28(LPQFATAAT)和GRA327-35(VPFVVFLVA)与HLAB0702显示出高亲和力结合，并从HLAB0702血清阳性者的PBMC中诱导产生干扰素γ。在此，我们对这些多肽进行了评估，以确定它们在给予佐剂后是否能在HLAB0702转基因小鼠的脾细胞中诱导干扰素-γ，并对后续的攻击具有保护作用。用ELISPOT和脾T淋巴细胞增殖实验鉴定产生γ多肽的T细胞。用其中一个表位GRA720-28免疫HLAB*0702小鼠，GRA720-28与一个通用的CD4+T细胞表位(PADRE)和佐剂(CD4+T细胞佐剂、GLASE和刺激CD8+T细胞的Pam2Cys)联合免疫，这种免疫诱导CD8+T细胞产生干扰素-γ，并保护小鼠免受高寄生虫感染。这项工作证明了生物信息学的可行性，然后以基于人类白细胞抗原结合的经验方法来测试这种生物学活性，以识别保护性的人类白细胞抗原-B*0702限制性弓形虫多肽和佐剂，从而在人类白细胞抗原-B*0702小鼠中诱导保护性免疫反应。
Ability of CD8+ T cells to act as cytolytic effectors and produce IFN-γ was shown to mediate resistance to Toxoplasma gondii in murine models due to recognition of peptides restricted by murine MHC Class I molecules. However, no T. gondii specific HLA-B07 restricted peptides were proven protective against T gondii. Recently, two T gondii-specific HLA-B*0702-restricted T cell epitopes, GRA720–28 (LPQFATAAT) and GRA327–35 (VPFVVFLVA), displayed high-affinity binding to HLA-B*0702, and elicited IFN-γ from PBMCs of seropositive HLA-B*0702 persons. Herein, these peptides were evaluated to determine whether they could elicit IFN-γ in splenocytes of HLA-B*0702 transgenic mice when administered with adjuvants and protect against subsequent challenge. Peptide-specific IFN-γ producing T cells were identified by ELISPOT and proliferation assays utilizing splenic T lymphocytes from HLA transgenic mice. When HLA-B*0702 mice were immunized with one of the epitopes identified, GRA720–28 in conjunction with a universal CD4+ T cell epitope (PADRE) and adjuvants (CD4+ T cell adjuvant, GLA-SE, and TLR2 stimulatory Pam2Cys for CD8+ T cells), this immunization induced CD8+ T cells to produce IFN-γ and protected mice against high parasite burden when challenged with T gondii. This work demonstrates feasibility of bioinformatics followed by an empirical approach based on HLA binding to test this biological activity for identifying protective HLA-B*0702 restricted T gondii peptides and adjuvants that elicit protective immune responses in HLA-B*0702 mice.
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