The HIV-1HLA-A2-SLYNTVATL is a help-independent CTL epitope
The HIV-1HLA-A2-SLYNTVATL is a help-independent CTL epitope
复制标题
DOI：
10.4049/jimmunol.172.9.5249
复制
发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Bereta, M
中科院分区：
文献类型：
--
作者：
Kan-Mitchell, J;Bisikirska, B;Bereta, M
针对 HLA-A*0201 限制性 HIV-1 p17 Gag(77-85) 表位（SLYNTVATL；SL9）的 CTL 反应已在患者中进行了广泛研究。尽管这种反应性在慢性感染患者中异常突出，并且与病毒载量呈负相关，但在急性感染中很少检测到 SL9 特异性 CTL (SL9-CTL)。为了探索这种不寻常表现的细胞基础，我们从健康、血清阴性供体的初始循环 CD8(+) T 细胞中体外引发了 SL9-CTL，并对其进行了表征。 SL9 似乎在几个重要方面不同于其他经过充分研究的 A*0201 限制性表位。与已发表的流感和黑色素瘤肽以及此处平行研究的 HIV gag IV9 表位的报告相反，SL9-CTL 是由未成熟但不成熟的自体树突细胞引发的。高度激活的 SL9-CTL 产生足够的自分泌介质，在没有 CD4(+) T 细胞或外源性 IL-2 的情况下维持克隆扩增和 CTL 分化数月。此外，SL9-CTL 对旁分泌 IL-2 诱导的细胞凋亡敏感。 IL-2 独立性和对旁分泌 IL-2 的敏感性也是由编码全长 Gag 的非复制慢病毒载体转导的树突状细胞免疫的 SL9-CTL 的特征。体外引发的 SL9-CTL 类似于来自对 SL9 和 SL9 的识别和功能亲和力退化的患者的那些。它的自然突变。总之，这些数据表明 SL9 是一种高度免疫原性、不依赖于帮助的 HIV 表位。急性感染时SL9-CTL的缺乏可能是由于先天免疫的强烈激活导致细胞因子诱导的细胞凋亡。相比之下，在 CD4 减少的慢性感染期间，持续产生自分泌帮助的 SL9-CTL 将占主导地位。
The CTL response to the HLA-A*0201-restricted, HIV-1 p17 Gag(77-85) epitope (SLYNTVATL; SL9) has been extensively studied in patients. Although this reactivity is exceptionally prominent in chronically infected patients and inversely correlated to viral load, SL9-specific CTLs (SL9-CTLs) are rarely detected in acute infection. To explore the cellular basis for this unusual manifestation, SL9-CTLs primed ex vivo from naive circulating CD8(+) T cells of healthy, seronegative donors were generated and characterized. SL9 appeared to differ from other well-studied A*0201-restricted epitopes in several significant respects. In contrast to published reports for influenza and melanoma peptides and the HIV gag IV9 epitope studied here in parallel, SL9-CTLs were primed by immature but not mature autologous dendritic cells. Highly activated SL9-CTLs produce sufficient autocrine mediators to sustain clonal expansion and CTL differentiation for months without CD4(+) T cells or exogenous IL-2. Moreover, SL9-CTLs were sensitive to paracrine IL-2-induced apoptosis. IL-2 independence and sensitivity to paracrine IL-2 were also characteristic of SL9-CTLs immunized by dendritic cells transduced by a nonreplicating lentiviral vector encoding full-length Gag. In vitro-primed SL9-CTLs resembled those derived from patients in degeneracy of recognition and functional avidities for both SL9 and. its natural mutations. Together, these data show that SL9 is a highly immunogenic, help-independent HIV epitope. The scarcity of SL9-CTLs in acute infection may result from cytokine-induced apoptosis with the intense activation of the innate immunity. In contrast, SL9-CTLs that constitutively produce autocrine help would predominate during CD4-diminished chronic infection.