TCR测序，怎么哪哪都有你?
T细胞受体，即T细胞抗原受体(T cell receptor，TCR): 是T细胞特异性识别和结合抗原肽-MHC分子的分子结构， 通常与CD3分子呈复合物形式存在于T细胞表面。大多数T细胞的TCR由α和β肽链组成，少数T细胞的TCR由γ和δ肽链组成。
β链的CDR3区的多样性使得T细胞能识别各种各样的抗原。CDR3多样性主要是T细胞在重组酶RAG1和RAG2催化作用下，通过体细胞V(D)J基因重排产生。TCRα 链通过VJ重组产生，而β链通过VDJ重组产生。V、D、J基因片段本身具有多样性，此外在重排的过程中，在V-D及D-J的连接区经常有非模板的核苷酸随机插入或删除，进一步增加了CDR3区的多样性，以识别不同的抗原。
TCR的复杂度和多样性不仅影响肿瘤细胞的识别、与免疫治疗相关，异常的TCR多样性还影响自身免疫疾病、免疫缺陷疾病、过敏反应、器官移植排斥等多种疾病的发生、发展。
今天我们就来说一说TCR测序的应用。
对治疗的反应监控、评估
· 监控联合使用免疫检查点抑制剂（PD-1和CTLA-4）对治疗爆发性心肌炎、黑色素瘤（Fulminant Myocarditis）效果。
Fulminant Myocarditis with Combination Immune Checkpoint Blockade.November, 2016
TCR beta sequencing to determine clonal T-cell populations in melanoma patients undergoing immunotherapy. ICI 2016 | August, 2016
· 监测免疫检查点抑制剂CTLA-4治疗前列腺病（ prostate cancer）、早期乳腺癌（breast cancer）的效果。
Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. PNAS | October, 2016
Deep Sequencing of T-Cell Receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy. Cancer Immunology Research | September, 2016
· 评估PD-1抑制剂对免疫系统副作用反应。
PD-1 blockade induces responses by inhibiting adaptive immune resistance.Nature | November, 2014
· 联合PD-L1和单抗对转移性肾瘤的治疗监控
Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature Communications | August, 2016
· 评估使用DC疫苗和肿瘤浸润细胞回输方法对治疗恶性黑色素瘤的效果
A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma Cancer Immunology. Immunotherapy | November, 2014
· 监测VGX-3100疫苗（DNA免疫治疗药物）用于宫颈上皮内瘤变（(HPV)16/18-positive CIN2/3），指导用药
Augmentation of cellular and humoral immune responses to HPV16 and HPV18 E6 and E7 antigens by VGX-3100. |September, 2016
· 对使用传统化疗方法治疗B细胞淋巴瘤效果的评价
The T-cell receptor repertoire influences the tumor microenvironment and is associated with survival in aggressive B-cell lymphoma Clinical Cancer. Research | September, 2016
· 监测使用AM0010（增强CD8 T细胞的存活率及其杀伤活性） 治疗胰腺癌或结直肠癌（pancreatic or colorectal cancer）的效果
Anti-tumor activity of PEGylated human IL-10 (AM0010) in patients with pancreatic or colorectal cancer. 2016 ASCO Annual Meeting | June, 2016
· 监控病毒感染后T细胞的动态反应，可指导设计有效疫苗
Dynamics of the Cytotoxic T Cell Response to a Model of Acute Viral Infection J Virol. | February, 2015
· 监控CD40抗体治疗转移性黑色素瘤的完全缓释进程
Immune activation and a 9-year ongoing complete remission following CD40 antibody therapy and metastasectomy in a patient with metastatic melanoma
Cancer Immunology Research | November, 2014
· 监控调节性T细胞治疗方法对抗宿主病的治疗效果
Clinical Grade Manufacturing of Human Alloantigen-Reactive Regulatory T Cells for Use in Transplantation. American Journal of Transplantation | September, 2013
疾病诊断
· CD8 T细胞淋巴白血病（CD8 T-large granular lymphocyte leukemia）诊断和疾病进展监控。
Deep sequencing of the T cell receptor repertoire in CD8 T-large granular lymphocyte leukemia identifies signature landscapes. Blood | December, 2013
· 皮肤T细胞淋巴癌（Cutaneous T Cell Lymphoma）早期诊断和MRD检测。
TCR Sequencing Facilitates Diagnosis and Identifies Mature T Cells as the Cell of Origin in CTCL. Science Translational Medicine | October, 2015
Minimal Residual Disease Monitoring with High-Throughput Sequencing of T Cell Receptors in Cutaneous T Cell Lymphoma. Science Translational Medicine | December, 2013
· 从多肌炎到癌变的预测、检测。
Peripheral T-cell lymphoma emerging in a patient with aggressive polymyositis: molecular evidence for neoplastic transformation of an oligoclonal T-cell infiltrate. Acta Neuropathologica | October, 2013
· T细胞淋巴癌和白血病（T cell leukemias and lymphomas）的诊断以及治疗后监控。
Detecting and monitoring lymphoma with high-throughput sequencing. Oncotarget | April, 2011
免疫缺陷
· 无症状LIG4综合征免疫分型检测。
Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals. Journal of Clinical Immunology | May, 2016
· 普通变异性免疫缺陷病(common variable immunodeficiency，CVID)检测。
Clonal and constricted T cell repertoire in Common Variable Immune Deficiency. Clinical Immunology | January, 2015
· HIV-1病人疾病的恶化监控。
IL-15 promotes activation and expansion of CD8 T cells in HIV-1 infection. JCI | June, 2016
肿瘤
· 肺结核疫苗（新药）评价。
Human and Murine Clonal CD8 T Cell Expansions Arise During Tuberculosis Because of TCR Selection. PLOS Pathogens | May, 2015
· 通过对肿瘤润侵T细胞受体测序为肿瘤病人个性化照料提供依据。
Tumor-Associated Immune Parameters for Personalized Patient Care Science. Translational Medicine | December, 2013
· T细胞治疗效果监控。
High-content molecular profiling of T-cell therapy in oncology Molecular Therapy - Oncolytics | May, 2016
· 胶质瘤DC疫苗效果预测。
TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination. Cancer Immunology Research | March, 2016
自身免疫和炎症疾病
· 先天性关节炎和类风湿性关节炎非侵入性（相对于关节腔液检查）检测。
TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis. Annals of Rheumatic Disease | June, 2016
· IgG4相关性疾病（IgG4-RD）的诊断。
Clonal expansion of CD4 cytotoxic T lymphocytes in patients with IgG4-related disease. The Journal of Allergy and Clinical Immunology | March, 2016
移植免疫
· 对移植术后环磷酰胺（PTCy）预防移植物抗宿主病(GVHD)的效果监控。
Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. Journal of Clinical Investigation - Insight | May, 2016
· 脐带血造血干细胞移植后免疫重建的监控，评估干细胞移植后细胞免疫力重建程度，用于指导后天性或先天性免疫抑制患者的临床决策
Correlation of TCR diversity with immune reconstitution after cord blood transplant.2012 American Society of Clinical Oncology Annual Meeting | May, 2012
TCR Repertoire Diversity Assessed with Immunosequencing is Associated with Patient Mortality Following Cord Blood Transplant. 2015 European Hematology Association Congress | June, 2015
Evolution and Clinical Implications of the T cell Repertoire Following Cord Blood Transplant. Biology of Blood and Marrow Transplantation | February, 2013
· 肾脏和骨髓移植（CKBMT）后免疫耐受的生物标记物检测。
Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients. Science Translational Medicine | January, 2015
看了这些，你是否感受到TCR测序无处不在？T细胞受体测序(TCR seq)，结合高通量测序技术，结合生物信息学分析手段，分析VDJ重排的方式等，广泛应用于肿瘤免疫、自身免疫性疾病、器官移植免疫监测免疫监测等领域。
TCR测序的应用今天就策到这里，下期BCR测序应用我们再见
ImmuHubTM是由艾沐蒽开发的一套灵活度极高的TCR和BCR二代测序平台。可根据不同样本类型和课题的需求为客户提供个性化的文库构建（5race或多重PCR方法）和测序模式（Hiseq或Miseq），并配合世界领先的生物信息学算法提供可视化数据分析。
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