HLA tapasin independence: broader peptide repertoire and HIV control.
HLA tapasin independence: broader peptide repertoire and HIV control.
复制标题
DOI：
10.1073/pnas.2013554117
复制
发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Carrington M
中科院分区：
文献类型：
--
作者：
Bashirova AA;Viard M;Naranbhai V;Grifoni A;Garcia-Beltran W;Akdag M;Yuki Y;Gao X;O'hUigin C;Raghavan M;Wolinsky S;Bream JH;Duggal P;Martinson J;Michael NL;Kirk GD;Buchbinder SP;Haas D;Goedert JJ;Deeks SG;Fellay J;Walker B;Goulder P;Cresswell P;Elliott T;Sette A;Carlson J;Carrington M
HLA I类分子结合抗原肽并将其呈递到细胞毒性T细胞的细胞表面上以引发免疫应答。肽的选择过程在一种叫做tapasin的分子的帮助下在细胞内发生。HLA I类分子是高度可变的，这影响它们的结构特征和tapasin参与肽选择的水平。我们测量了近100种HLA变体的tapasin依赖性水平，发现tapasin依赖性水平与HLA I类分子呈递给T细胞的肽的数量呈负相关，从而影响免疫应答的广度。HIV队列中HLA基因型的分析表明，更大的tapasin独立性与更慢的疾病进展和更低的病毒载量相关。人类白细胞抗原（HLA）I类同种异型在缺乏tapasin（肽加载复合物的必要组分）的情况下呈递肽的能力不同。我们量化了在欧洲和非洲裔美国人中常见的所有同种异型的tapasin依赖性（n = 97），这揭示了广泛的连续值。对来自感染受试者的整个HIV-1蛋白质组的细胞毒性T细胞应答的离体检查表明，Tapasin依赖的同种异型比Tapasin独立的同种异型呈现更有限的一组不同的肽，数据得到计算预测的支持。这表明tapasin依赖性的变化可能通过改变肽库大小来影响免疫应答的强度。为了支持这一模型，我们观察到携带HLA I类基因型的个体，其特征在于具有更大的tapasin独立性，进展更慢，并保持较低的病毒载量，这可能是由于肽呈递的宽度增加。因此，tapasin依赖性水平，如HLA接合性，可以作为限制或扩大人类HLA-I肽库宽度的手段，最终影响对病原体和疫苗的免疫应答。
HLA class I molecules bind antigenic peptides and present them on the cell surface to cytotoxic T cells to initiate immune responses. The peptide selection process occurs intracellularly with the aid of a molecule called tapasin. HLA class I molecules are highly variable, which influences their structural characteristics and the level of tapasin involvement in peptide selection. We measured tapasin dependence levels of nearly 100 HLA variants and found that the level of tapasin dependence negatively correlates with the number of peptides that the HLA class I molecule presents to T cells, thereby affecting breadth of the immune response. Analysis of HLA genotypes in HIV cohorts reveals that greater tapasin independence associates with slower disease progression and lower viral load. Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.
登录
查看更多内容
影响因子：
32.4
作者：
Dong, Gang;Wearsch, Pamela A.;Peaper, David R.;Cresswell, Peter;Reinisch, Karin M.
通讯作者：
Reinisch, Karin M.
DOI：
10.4049/jimmunol.1700893
发表时间：
2017-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jurtz V;Paul S;Andreatta M;Marcatili P;Peters B;Nielsen M
通讯作者：
Nielsen M
影响因子：
30.5
作者：
Garcia-Beltran WF;Hölzemer A;Martrus G;Chung AW;Pacheco Y;Simoneau CR;Rucevic M;Lamothe-Molina PA;Pertel T;Kim TE;Dugan H;Alter G;Dechanet-Merville J;Jost S;Carrington M;Altfeld M
通讯作者：
Altfeld M
DOI：
10.1126/science.aac9475
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hansen SG;Wu HL;Burwitz BJ;Hughes CM;Hammond KB;Ventura AB;Reed JS;Gilbride RM;Ainslie E;Morrow DW;Ford JC;Selseth AN;Pathak R;Malouli D;Legasse AW;Axthelm MK;Nelson JA;Gillespie GM;Walters LC;Brackenridge S;Sharpe HR;López CA;Früh K;Korber BT;McMichael AJ;Gnanakaran S;Sacha JB;Picker LJ
通讯作者：
Picker LJ
影响因子：
11.4
作者：
Chen, Mingnan;Bouvier, Marlene
通讯作者：
Bouvier, Marlene