A Quantitative Analysis of Complexity of Human Pathogen-Specific CD4 T Cell Responses in Healthy M. tuberculosis Infected South Africans.
A Quantitative Analysis of Complexity of Human Pathogen-Specific CD4 T Cell Responses in Healthy M. tuberculosis Infected South Africans.
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DOI：
10.1371/journal.ppat.1005760
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发表时间：
2016-07
期刊：
影响因子：
6.7
通讯作者：
Sette A
中科院分区：
文献类型：
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作者：
Lindestam Arlehamn CS;McKinney DM;Carpenter C;Paul S;Rozot V;Makgotlho E;Gregg Y;van Rooyen M;Ernst JD;Hatherill M;Hanekom WA;Peters B;Scriba TJ;Sette A
我们进行了定量分析的HLA限制，抗原和抗原表位特异性的人类病原体特异性反应在健康人感染支原体。结核病（Mtb），在南非队列中作为测试病例。该结果首次在感染和人群背景下估计了T细胞反应的广度。我们确定了11种代表性Mtb抗原的表位库和一大组先前定义的Mtb表位。我们估计，我们的分析方法在63人的队列中检测到总应答的50-75%。正如预期的那样，反应是高度异质性的，共检测到125个表位的反应。在我们的研究中，66个最高表位提供了80%的应答覆盖率。使用一组48个HLA II类转染的抗原呈递细胞，我们确定了278个表位/供体识别事件（占总数的36%）的HLA II类限制。大多数表位受到多个HLA等位基因的限制，380种不同的表位/HLA组合仅占估计的Mtb特异性反应的不到30%。我们的研究结果强调了人类T细胞反应在群体水平上的复杂性。捕获和表征这种广泛且高度HLA混杂的Mtb特异性T细胞表位库的努力将需要显著的肽多重努力。我们表明，一个全面的“megapool”的结核分枝杆菌肽捕获了大部分的结核分枝杆菌特异性T细胞，并可用于表征这种反应。人类病原体特异性免疫反应非常复杂，研究它们的技术不断扩展。目前迫切需要对病原体特异性免疫反应进行定量分析和更好地了解。结核分枝杆菌（Mtb）是世界范围内因感染剂导致死亡的主要原因之一。在这里，我们能够量化来自南非的Mtb感染健康个体的Mtb特异性反应。反应是高度多样化的，需要66个表位来捕获80%的总反应性。我们的研究还表明，大多数已鉴定的表位受多个HLA等位基因的限制。因此，需要技术进步来捕获和表征完整的病原体特异性反应。该研究进一步证明，将鉴定的表位组合成“megapools”的方法允许捕获总反应性的大部分。这表明该技术通常适用于表征对其他复杂病原体的免疫力。总之，我们的数据首次提供了对复杂病原体特异性T细胞反应的定量分析，并提供了对自然感染环境中人类感染的新理解。
We performed a quantitative analysis of the HLA restriction, antigen and epitope specificity of human pathogen specific responses in healthy individuals infected with M. tuberculosis (Mtb), in a South African cohort as a test case. The results estimate the breadth of T cell responses for the first time in the context of an infection and human population setting. We determined the epitope repertoire of eleven representative Mtb antigens and a large panel of previously defined Mtb epitopes. We estimated that our analytic methods detected 50–75% of the total response in a cohort of 63 individuals. As expected, responses were highly heterogeneous, with responses to a total of 125 epitopes detected. The 66 top epitopes provided 80% coverage of the responses identified in our study. Using a panel of 48 HLA class II-transfected antigen-presenting cells, we determined HLA class II restrictions for 278 epitope/donor recognition events (36% of the total). The majority of epitopes were restricted by multiple HLA alleles, and 380 different epitope/HLA combinations comprised less than 30% of the estimated Mtb-specific response. Our results underline the complexity of human T cell responses at a population level. Efforts to capture and characterize this broad and highly HLA promiscuous Mtb-specific T cell epitope repertoire will require significant peptide multiplexing efforts. We show that a comprehensive “megapool” of Mtb peptides captured a large fraction of the Mtb-specific T cells and can be used to characterize this response. Human pathogen-specific immune responses are tremendously complex and the techniques to study them ever expanding. There is an urgent need for a quantitative analysis and better understanding of pathogen-specific immune responses. Mycobacterium tuberculosis (Mtb) is one of the leading causes of mortality due to an infectious agent worldwide. Here, we were able to quantify the Mtb-specific response in healthy individuals with Mtb infection from South Africa. The response is highly diverse and 66 epitopes are required to capture 80% of the total reactivity. Our study also show that the majority of the identified epitopes are restricted by multiple HLA alleles. Thus, technical advances are required to capture and characterize the complete pathogen-specific response. This study demonstrates further that the approach combining identified epitopes into “megapools” allows capturing a large fraction of the total reactivity. This suggests that this technique is generally applicable to the characterization of immunity to other complex pathogens. Together, our data provide for the first time a quantitative analysis of the complex pathogen-specific T cell response and provide a new understanding of human infections in a natural infection setting.