Viral Vaccine Program, Seattle Biomedical Research Institute (Seattle Biomed), Seattle, Washington, USA.
Nat Med. 2011 Jul 17;17(8):989-95. doi: 10.1038/nm.2422.
Specific human leukocyte antigens (HLAs), notably HLA-B27 and HLA-B57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8(+) T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B27 or HLA-B57 allele groups do not. Here we show that CD8(+) T cells restricted by 'protective' HLA allele groups are not suppressed by T(reg) cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8(+) T cells to T(reg) cell-mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B27- and HLA-B57-restricted effectors also evade T(reg) cell-mediated suppression by directly killing T(reg) cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B27 and HLA-B57 allele groups are associated with delayed HIV-1 disease progression.
特定的人类白细胞抗原（HLA），特别是 HLA-B27 和 HLA-B57 等位基因群，长期以来一直与 HIV-1 的控制有关。尽管大多数 HIV 特异性 CD8(+) T 细胞在慢性感染过程中丧失增殖能力，但受 HLA-B27 或 HLA-B57 等位基因群限制的 T 细胞不会。在这里，我们表明受“保护性”HLA 等位基因群限制的 CD8(+) T 细胞不受 T(reg)细胞的抑制，而在同一个体中，受“非保护性”等位基因限制的 T 细胞在体外受到高度抑制。HIV 特异性 CD8(+) T 细胞对 T(reg)细胞介导的抑制的这种差异敏感性与其在与同源表位刺激后表达抑制性受体 T 细胞免疫球蛋白结构域和粘蛋白结构域 3（Tim-3）有关。此外，我们还表明，HLA-B27 和 HLA-B57 限制的效应物还通过直接杀伤它们在 granzyme B (GzmB)-依赖性方式中遇到的 T(reg)细胞来逃避 T(reg)细胞介导的抑制。这项研究揭示了 HLA-B27 和 HLA-B57 等位基因群与 HIV-1 疾病进展延迟相关的一个以前未知的解释。
