Before the advent of NGS, immune repertoires were largely impenetrable, because it was not possible to enumerate a set of distinct T cells, or clonotypes, large enough to be a meaningful representation of the repertoire in its entirety. A completely analogous process occurs for the TCR α chain, without the D gene segment included.Īs in many areas of investigation, advances in next generation sequencing (NGS) technologies, in which sequences are decoded on arrays and many millions of sequences can be read simultaneously, have been transformative for immune repertoire analysis. The mechanism by which gene segments are joined also introduces base pair variability, which together with the combinatorial selection of these segments results in TCR diversity. Initially one of the two D regions is joined with one of 13 J regions (both randomly selected), followed by joining of the DJ region to one of more than 50 V regions (also randomly selected), yielding a final VDJ region that is approximately 500 bp in length. The TCR-β locus is located on chromosome 7 and is approximately 620 kb in length. (c) Simplified representation of TCR-β VDJ gene recombination resulting in TCR diversity. The CDR3 regions are the main domains of the TCR that are in contact with peptide antigen, and largely determine TCR specificity. Color gradients at junctions represent the regions encoded by arbitrary, untemplated nucleotides introduced during somatic recombination, and which represent a primary source of sequence diversification and TCR variability (see (c) for details). The complementarity determining region 3 (CDR3) domain, approximately 45 nucleotides long, comprises the VJ (for TCR-α) or VDJ (for TCR-β) junction. In TCR α chains the J region is followed by the V region (orange), whereas in TCR β chains, a D region is located between the V and J regions. Moving outward from the T cell, the constant region (green) of the TCR is anchored to the cell membrane, followed by the J region (red). (b) A TCR heterodimer, composed of an α and β chain, engaging peptide-MHC (pMHC). The T-cell receptor (TCR multi-colored) binds to both the antigen and MHC, and if the binding avidity is sufficiently high the T-cell is activated. The APC presents peptide antigen (Ag yellow) in complex with the larger major histocompatibility complex (MHC turquoise). (a) A T-cell (pink) encountering an antigen-presenting cell (APC blue). T-cell receptor-antigen-peptide-MHC interaction and TCR gene recombination. In this review, we introduce this nascent field and TCR-seq methodology, we discuss recent insights into healthy and diseased TCR repertoires, and we examine the applications and challenges for TCR-seq in the clinic. It is expected that maturation of the field will involve the introduction of improved, standardized tools for data handling, deposition and statistical analysis, as well as the emergence of new and equivalently large-scale technologies for T-cell functional analysis and antigen discovery. However, T-cell repertoire sequencing is still in its infancy. In the context of disease, TCR-seq has been instrumental in characterizing the recovery of the immune repertoire after hematopoietic stem cell transplantation, and the method has been used to develop biomarkers and diagnostics for various infectious and neoplastic diseases. TCR-seq studies have provided new insights into the healthy human T-cell repertoire, such as revised estimates of repertoire size and the understanding that TCR specificities are shared among individuals more frequently than previously anticipated. High-throughput TCR sequencing (TCR-seq) involves the use of next generation sequencing platforms to generate large numbers of short DNA sequences covering key regions of the TCR coding sequence, which enables quantification of T-cell diversity at unprecedented resolution. b_4()Īt .AsyncControllerActionInvoker.c_Displa圜lass3_1.T-cell antigen receptor (TCR) variability enables the cellular immune system to discriminate between self and non-self. b_2()Īt .AsyncControllerActionInvoker.EndInvokeActionMethodWithFilters(IAsyncResult asyncResult)Īt .AsyncControllerActionInvoker.c_Displa圜lass3_6. b_1(IAsyncResult asyncResult)Īt .AsyncControllerActionInvoker.EndInvokeActionMethod(IAsyncResult asyncResult)Īt ._Displa圜lass11_0. End of stack trace from previous location where exception was thrown -Īt .Throw()Īt .HandleNonSuccessAndDebuggerNotification(Task task)Īt .TaskAsyncActionDescriptor.EndExecute(IAsyncResult asyncResult)Īt .AsyncControllerActionInvoker.c_Displa圜lass8_0. d_24.MoveNext() in D:\MaverStation\WorkShop\BaiShiDeng\Wjgnet\BsdWebApp\BsdWebApp\Controllers\JournalController.cs:line 485 System.NullReferenceException: Object reference not set to an instance of an object.Īt.
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