Humoral immune responses in humanized BLT mice immunized with West Nile virus and HIV-1 envelope proteins are largely mediated via human CD5+ B cells
Humoral immune responses in humanized BLT mice immunized with West Nile virus and HIV-1 envelope proteins are largely mediated via human CD5+ B cells
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DOI：
10.1111/j.1365-2567.2011.03501.x
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发表时间：
2011-12-01
期刊：
影响因子：
6.4
通讯作者：
Marasco, Wayne A.
中科院分区：
文献类型：
--
作者：
Biswas, Subhabrata;Chang, Hong;Marasco, Wayne A.
BLT小鼠是通过手术植入人胎儿胸腺-肝组织并将自体CD34(+)造血干细胞静脉输送到成年非肥胖糖尿病/严重联合免疫缺陷小鼠体内而构建的，用于评估疫苗诱导的体液免疫反应。植入后，这些小鼠发育出了人类淋巴系统。然而，大多数外周人类 B 淋巴细胞表现出不成熟的表型，如表面 CD10 表达所证明的那样。超过 50% 的外周 B 细胞（但骨髓中不存在）也表达 CD5 抗原，这种抗原很少见于人类成熟滤泡 B 细胞中。使用重组病毒包膜抗原进行单次肌内免疫，例如。 g。 HIV-gp140 和西尼罗病毒包膜蛋白与免疫刺激性 IC31 (R) 佐剂一起导致血清转化，其特征是主要为 IgM 同种型的抗原特异性人类抗体。然而，重复加强免疫并没有诱导二次免疫反应，缺乏类别转换和特异性 IgM 水平保持相对不变就证明了这一点。有趣的是，外周CD19(+) CD5(+)而非CD19(+) CD5(-)人B淋巴细胞表现出晚期发育的CD27(+) IgM(+)记忆表型，这表明先前参与“天然抗体”产生的CD5(+) B细胞亚群可能在疫苗诱导的抗体反应中发挥作用。此外，这些小鼠的人 T 淋巴细胞表现出次优的增殖反应和离体共刺激表面蛋白的丧失，而人白细胞介素 2 和白细胞介素 7 可以部分逆转这种情况。因此，BLT 小鼠中疫苗诱导的免疫反应类似于不依赖于 T 细胞的途径，可以通过外源性输送人类细胞因子/生长因子在体内进行调节。
BLT mice, constructed by surgical implantation of human fetal thymus-liver tissues and intravenous delivery of autologous CD34(+) haematopoietic stem cells into adult non-obese diabetic/severe combined immunodeficiency mice, were evaluated for vaccine-induced humoral immune responses. Following engraftment, these mice developed a human lymphoid system; however, the majority of the peripheral human B lymphocytes displayed an immature phenotype as evidenced by surface CD10 expression. Over 50% of the human B cells in the periphery but not in the bone marrow also expressed the CD5 antigen, which is found only infrequently on mature follicular B cells in humans. A single intramuscular immunization with recombinant viral envelope antigens, e. g. HIV-gp140 and West Nile Virus envelope proteins, together with the immune stimulatory IC31 (R) adjuvant resulted in seroconversion characterized by antigen-specific human antibodies predominantly of the IgM isotype. However, repeated booster immunizations did not induce secondary immune responses as evidenced by the lack of class switching and specific IgM levels remaining relatively unchanged. Interestingly, the peripheral CD19(+) CD5(+) but not the CD19(+) CD5(-) human B lymphocytes displayed a late developing CD27(+) IgM(+) memory phenotype, suggesting that the CD5(+) B-cell subset, previously implicated in 'natural antibody' production, may play a role in the vaccine-induced antibody response. Furthermore, human T lymphocytes from these mice demonstrated suboptimal proliferative responses and loss of co-stimulatory surface proteins ex vivo that could be partially reversed with human interleukin-2 and interleukin-7. Therefore, vaccine-induced immune responses in BLT mice resemble a T-cell-independent pathway that can potentially be modulated in vivo by the exogenous delivery of human cytokines/growth factors.