Development of killer T cell vaccine against HCV env HVRI

来自丙型肝炎病毒（HCV）包膜蛋白的高变区-1 （HVR1）被认为是中和抗体的靶标。为了探索辅助性T细胞对HVR1的识别及其在抗体应答中的作用，我们试图在三种MHC类型的小鼠和来自hcv感染的hla多样化的人的PBMC中产生特异性的HVR1辅助性T细胞。在这两个物种中，HVR1通过>1 II类MHC分子呈递到CD4^+辅助性T细胞，并表现出惊人的分离间交叉反应性。两名DR4^+患者的表位被定位到一个包含DR4结合基序的更保守的c端序列，这可能是交叉反应性的原因。引人注目的是，针对患者自身HVR1序列的抗体仅在对HVR1有反应的患者中发现，尽管所有患者都有包膜蛋白抗体，这表明HVR1抗体的诱导依赖于抗体表位附近序列特异性的辅助T细胞。因此，HVR1特异性辅助性T细胞在诱导中和HCV抗体方面可能具有重要的功能。这些结果可能是“T- b互惠”的第一个例子，在人类疾病环境中，辅助T细胞表位的邻近性决定了抗体表位的特异性。

Hypervariable region-1 (HVR1) from the hepatitis C virus (HCV) envelope protein is thought to be a target for neutralizing antibodies. To explore HVR1 recogntion by helper T cells, and their role in antibody responses, we attempted to generate helper T cells specific for HVR1 in mice of three MHC types, and with PBMC from HCV-infected HLA-diverse humans. In both species, HVR1 was presented by >1 class II MHC molecule to CD4^+ helper T cells and showed surprising interisolate crossreactivity. The epitope for two DR4^+ patients was mapped to a more conserved C-terminal sequence containing a DR4 binding motif, possibly accounting for crossreactivity. Strikingly, antibodies to patients' own HVR1 sequences were found only in patients with T cell responses to HVR1, even though all had antibodies to envelope protein, suggesting that induction of antibodies to HVR1 depends on helper T cells specific for a sequence proximal to the antibody epitope. Thus, helper T cells specific for HVR1 may be functionally important in inducing neutralizing antibodies to HCV.These results may be the first example of "T-B reciprocity, " in which proximity of a helper T cell epitope determines antibody epitope specificity, in a human disease setting.