Lindestam Arlehamn Cecilia S, Sette Alessandro
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA , USA.
Front Immunol. 2014 Mar 24;5:124. doi: 10.3389/fimmu.2014.00124. eCollection 2014.
We have recently described the first true genome-wide screen for CD4(+) T-cell reactivity directed against Mycobacterium tuberculosis (MTB) in latent TB-infected individuals. The approach relied on predictions of HLA-binding capacity for a panel of DR, DP, and DQ alleles representative of those most commonly expressed in the general population, coupled with high throughput ELISPOT assays. The results identified hundreds of novel epitopes and antigens, and documented the novel observation that T cells in latent MTB infection are confined to the CXCR3(+)CCR6(+) phenotype and largely directed against three antigenic "islands" within the MTB genome. In parallel, we have made generally available to the scientific community the technical approaches and reagents developed in the process, such as motifs, algorithms, and binding assays for several common HLA class II alleles, and a panel of single allele HLA class II transfected cell lines representative of the most frequent specificities in the general population. Recent efforts have been focused on characterization of epitopes and antigens recognized by patients with active TB and individuals vaccinated with BCG, with the aim of providing the first systematic evaluation of the overlap between latent, active, and BCG cohorts. The definition of a broad range of epitopes restricted by common HLA molecules, will facilitate development of diagnostic reagents, allow a rigorous evaluation of T-cell responses associated with TB infection in humans, and enable the evaluation of the immunogenicity of different vaccine candidates. Furthermore, it might suggest new candidates for vaccine and diagnostic development.
我们最近描述了首个针对潜伏性结核感染个体中针对结核分枝杆菌（MTB）的CD4(+) T细胞反应性进行的真正全基因组筛选。该方法依赖于对一组代表一般人群中最常表达的DR、DP和DQ等位基因的HLA结合能力的预测，以及高通量ELISPOT检测。结果鉴定出数百个新表位和抗原，并记录了一个新发现，即潜伏性MTB感染中的T细胞局限于CXCR3(+)CCR6(+)表型，并且主要针对MTB基因组内的三个抗原“岛”。同时，我们已将在此过程中开发的技术方法和试剂普遍提供给科学界，例如几种常见HLA II类等位基因的基序、算法和结合检测，以及一组代表一般人群中最常见特异性的单等位基因HLA II类转染细胞系。最近的工作重点是对活动性结核患者和接种卡介苗个体所识别的表位和抗原进行表征，目的是首次系统评估潜伏性、活动性和卡介苗队列之间的重叠情况。定义一系列受常见HLA分子限制的表位，将有助于诊断试剂的开发，允许对与人类结核感染相关的T细胞反应进行严格评估，并能够评估不同候选疫苗的免疫原性。此外，这可能会为疫苗和诊断开发提出新的候选物。
