Bloomberg~Kimmel Institute for Cancer Immunotherapy.
Sidney Kimmel Comprehensive Cancer Center.
J Clin Invest. 2021 May 17;131(10). doi: 10.1172/JCI146922.
BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.
最近的研究报告称，在未接触过 SARS-CoV-2 的供体中存在针对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的 T 细胞免疫，这可能是由于 T 细胞对普通感冒冠状病毒（CCCs）的交叉识别。真正的 T 细胞交叉反应性，定义为单个 TCR 识别一种以上独特的肽-MHC 配体，在 SARS-CoV-2 的背景下从未被证明过。
我们使用病毒特异性 T 细胞的功能扩展（ViraFEST）平台，在康复期 COVID-19 患者（CCPs）和 SARS-CoV-2 未接触供体中，以 TCR 克隆型水平鉴定针对 SARS-CoV-2 和 CCCs 的刺突（S）糖蛋白具有交叉反应性的 T 细胞反应。使用 TCR 克隆和转染系统对 SARS-CoV-2/CCC 交叉反应性和功能亲和力的评估进行了确认。
在 65%的 CCPs 和未接触供体中检测到交叉识别 SARS-CoV-2 和至少一种其他 CCC 的 S 蛋白的记忆 CD4+T 细胞克隆型。这些 TCR 中的一些在多个供体中共享。与单特异性 CD4+T 细胞相比，交叉反应性 T 细胞在体外对 SARS-CoV-2 的特异性增殖显著受损，这与它们的 TCR 对 SARS-CoV-2 的功能亲和力低于 CCC 一致。
我们的数据首次证实了存在独特的记忆 CD4+T 细胞克隆型，这些克隆型可交叉识别 SARS-CoV-2 和 CCC。交叉反应性 TCR 对 SARS-CoV-2 的低亲和力可能是抗原印记的结果，即先前存在的 CCC 特异性记忆 T 细胞在 SARS-CoV-2 感染后扩张能力降低。需要进一步的研究来确定这些交叉反应性 T 细胞反应如何影响 COVID-19 患者的临床结果。
本研究由美国国立过敏和传染病研究所、美国国立癌症研究所和美国国立生物医学影像与生物工程研究所的 U54CA260492、P30CA006973、P41EB028239、R01AI153349、R01AI145435-A1、R21AI149760 和 U19A1088791 资助。彭博~金梅尔癌症免疫治疗研究所、约翰霍普金斯大学教务长和比尔及梅琳达盖茨基金会为这项研究提供了资金。
