Harada Mamoru, Gohara Rumi, Matsueda Satoko, Muto Akira, Oda Tatsuya, Iwamoto Yoshiko, Itoh Kyogo
Department of Immunology, Kurume University School of Medicine, Fukuoka, Japan.
J Immunol. 2004 Feb 15;172(4):2659-67. doi: 10.4049/jimmunol.172.4.2659.
Vaccination with class I tumor peptides has been performed to induce tumor-reactive CD8(+) T cells in vivo. However, the kinds of immune responses that vaccination might elicit in patients are not fully understood. In this study we tried to elucidate the mechanisms by which vaccination of class I binding tumor peptides into an HLA-A2(+) lung cancer patient elicited dramatic amounts of IgG1 and IgG2 specific to a nonamer peptide, ubiquitin-conjugated enzyme variant Kua (UBE2V)(43-51). The UBE2V(43-51) peptide contains cysteine at the sixth position. HLA-DR-restricted and UBE2V(43-51) peptide-recognizing CD4(+) T cells were induced from postvaccination, but not from prevaccination, PBMCs of the cancer patient. In addition, a CD4(+) T cell line (UB-2) and its clone (UB-2.3), both of which recognize the UBE2V(43-51) peptide in the context of HLA-DRB1*0403 molecules, were successfully established from postvaccination PBMCs. The peptide vaccination increased the frequency of peptide-specific T cells, especially CD4(+) T cells. In contrast, mass spectrometric analysis revealed that the vaccinated UBE2V(43-51) peptide contained both monomeric and dimeric forms. Both forms, fractionated by reverse phase HPLC, were recognized by UB-2 and UB-2.3 cells. Recognition by these CD4(+) T cells was observed despite the addition of a reduction reagent or the fixation of APC. Overall, these results indicate that vaccination with class I tumor peptides can induce HLA-DR-restricted CD4(+) T cells in vivo and elicit humoral immune responses, and that a cysteine-containing peptide can be recognized by CD4(+) T cells not only as a monomer, but also as a dimer.
已进行了I类肿瘤肽疫苗接种，以在体内诱导肿瘤反应性CD8(+) T细胞。然而，疫苗接种在患者体内可能引发的免疫反应类型尚未完全明确。在本研究中，我们试图阐明将I类结合肿瘤肽接种到一名HLA-A2(+)肺癌患者体内后，引发大量针对九聚体肽泛素结合酶变体Kua (UBE2V)(43 - 51)的IgG1和IgG2的机制。UBE2V(43 - 51)肽的第六位含有半胱氨酸。从接种疫苗后的癌症患者外周血单核细胞（PBMC）中诱导出了HLA-DR限制且识别UBE2V(43 - 51)肽的CD4(+) T细胞，而接种疫苗前的PBMC中未诱导出此类细胞。此外，从接种疫苗后的PBMC中成功建立了一个CD4(+) T细胞系（UB - 2）及其克隆（UB - 2.3），它们在HLA-DRB1*0403分子的背景下均能识别UBE2V(43 - 51)肽。肽疫苗接种增加了肽特异性T细胞的频率，尤其是CD4(+) T细胞。相比之下，质谱分析显示接种的UBE2V(43 - 51)肽包含单体和二聚体形式。通过反相高效液相色谱分离的这两种形式均能被UB - 2和UB - 2.3细胞识别。尽管添加了还原试剂或固定了抗原呈递细胞（APC），仍观察到这些CD4(+) T细胞的识别作用。总体而言，这些结果表明，I类肿瘤肽疫苗接种可在体内诱导HLA-DR限制的CD4(+) T细胞并引发体液免疫反应，且含半胱氨酸的肽不仅能被CD4(+) T细胞识别为单体，还能被识别为二聚体。
