Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8+ T Cell Responses
Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8+ T Cell Responses
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DOI：
10.1128/jvi.02355-10
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发表时间：
2011-04-01
影响因子：
5.4
通讯作者：
O'Connor, David H.
中科院分区：
文献类型：
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作者：
Budde, Melisa L.;Lhost, Jennifer J.;O'Connor, David H.
猴免疫缺陷病毒（SIV）感染的猕猴是诱导CD 8（+）T细胞应答的人类免疫缺陷病毒（HIV）疫苗的首选动物模型。与人类不同，人类的CD 8（+）T细胞反应受到最多6个HLA I类等位基因的限制，猕猴表达多达20种不同的主要组织相容性复合体I类（MHC-I）序列。有趣的是，只有猕猴MHC-I序列的一个子集在外周血淋巴细胞中转录丰富。我们假设高度转录的MHC-I序列主要负责限制SIV特异性CD 8（+）T细胞反应。为了验证这一假设，我们测量了MHC-I纯合型猕猴中SIV特异性CD 8（+）T细胞反应。通过全蛋白组γ干扰素（IFN-γ）酶联免疫斑点（ELISPOT）测定确定的8种CD 8（+）T细胞应答中的每一种都受到5种转录丰富（外周血淋巴细胞中总MHC-I转录物>1%）的转录物中的4种的限制。这些动物共有的五种转录罕见转录物并没有限制任何可检测的CD 8（+）T细胞应答。此外，通过鉴定M3单倍型上三种最常见的MHC-I转录物的肽结合基序，确定了七种CD 8（+）T细胞应答。这些结果表明，转录丰富的MHC-I转录本是限制SIV特异性CD 8（+）T细胞应答的主要原因。因此，只有猕猴中数千种已知的MHC-I等位基因的一个子集应该优先用于CD 8（+）T细胞表位表征。
Simian immunodeficiency virus (SIV)-infected macaques are the preferred animal model for human immunodeficiency virus (HIV) vaccines that elicit CD8(+) T cell responses. Unlike humans, whose CD8(+) T cell responses are restricted by a maximum of six HLA class I alleles, macaques express up to 20 distinct major histocompatibility complex class I (MHC-I) sequences. Interestingly, only a subset of macaque MHC-I sequences are transcriptionally abundant in peripheral blood lymphocytes. We hypothesized that highly transcribed MHC-I sequences are principally responsible for restricting SIV-specific CD8(+) T cell responses. To examine this hypothesis, we measured SIV-specific CD8(+) T cell responses in MHC-I homozygous Mauritian cynomolgus macaques. Each of eight CD8(+) T cell responses defined by full-proteome gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay were restricted by four of the five transcripts that are transcriptionally abundant (>1% of total MHC-I transcripts in peripheral blood lymphocytes). The five transcriptionally rare transcripts shared by these animals did not restrict any detectable CD8(+) T cell responses. Further, seven CD8(+) T cell responses were defined by identifying peptide binding motifs of the three most frequent MHC-I transcripts on the M3 haplotype. Combined, these results suggest that transcriptionally abundant MHC-I transcripts are principally responsible for restricting SIV-specific CD8(+) T cell responses. Thus, only a subset of the thousands of known MHC-I alleles in macaques should be prioritized for CD8(+) T cell epitope characterization.