Lewinsohn Deborah A, Swarbrick Gwendolyn M, Park Byung, Cansler Meghan E, Null Megan D, Toren Katelynne G, Baseke Joy, Zalwango Sarah, Mayanja-Kizza Harriet, Malone LaShaunda L, Nyendak Melissa, Wu Guanming, Guinn Kristi, McWeeney Shannon, Mori Tomi, Chervenak Keith A, Sherman David R, Boom W Henry, Lewinsohn David M
Division of Infectious Diseases, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
NPJ Vaccines. 2017;2. doi: 10.1038/s41541-017-0008-6. Epub 2017 Apr 3.
Despite widespread use of the Bacillus Calmette-Guerin vaccine, tuberculosis, caused by infection with , remains a leading cause of morbidity and mortality worldwide. As CD8 T cells are critical to tuberculosis host defense and a phase 2b vaccine trial of modified vaccinia Ankara expressing Ag85a that failed to demonstrate efficacy, also failed to induce a CD8 T cell response, an effective tuberculosis vaccine may need to induce CD8 T cells. However, little is known about CD8, as compared to CD4, antigens in tuberculosis. Herein, we report the results of the first ever HLA allele independent genome-wide CD8 antigen discovery program. Using CD8 T cells derived from humans with latent tuberculosis infection or tuberculosis and an interferon-γ ELISPOT assay, we screened a synthetic peptide library representing 10% of the proteome, selected to be enriched for antigens. We defined a set of immunodominant CD8 antigens including part or all of 74 proteins, only 16 of which are previously known CD8 antigens. Immunogenicity was associated with the degree of expression of mRNA and protein. Immunodominant antigens were enriched in cell wall proteins with preferential recognition of Esx protein family members, and within proteins comprising the secretome. A validation study of immunodominant antigens demonstrated that these antigens were strongly recognized in -infected individuals from a tuberculosis endemic region in Africa. The tuberculosis vaccine field will likely benefit from this greatly increased known repertoire of CD8 immunodominant antigens and definition of properties of proteins important for CD8 antigenicity.
尽管卡介苗已广泛使用，但由结核分枝杆菌感染引起的结核病仍是全球发病和死亡的主要原因。由于CD8 T细胞对结核病宿主防御至关重要，且一项表达Ag85a的改良安卡拉痘苗2b期疫苗试验未能证明其有效性，同时也未能诱导CD8 T细胞反应，因此有效的结核病疫苗可能需要诱导CD8 T细胞。然而，与CD4相比，人们对结核病中CD8抗原知之甚少。在此，我们报告了首个不依赖HLA等位基因的全基因组CD8抗原发现计划的结果。我们使用来自潜伏性结核感染或结核病患者的CD8 T细胞以及干扰素-γ ELISPOT检测法，筛选了一个代表蛋白质组10%的合成肽库，该肽库经筛选富集了结核分枝杆菌抗原。我们定义了一组免疫显性CD8抗原，包括74种结核分枝杆菌蛋白的部分或全部，其中只有16种是先前已知的CD8抗原。免疫原性与mRNA和蛋白质的表达程度相关。免疫显性抗原在细胞壁蛋白中富集，对Esx蛋白家族成员有优先识别，且在构成结核分枝杆菌分泌组的蛋白质中也有富集。对免疫显性抗原的验证研究表明，这些抗原在非洲结核病流行地区的结核分枝杆菌感染个体中得到了强烈识别。结核病疫苗领域可能会从这一大幅增加的已知CD8免疫显性抗原库以及对结核分枝杆菌蛋白对CD8抗原性重要特性的定义中受益。
