Linking T cell receptor sequence to T cell function

将 T 细胞受体序列与 T 细胞功能联系起来

• 批准号: RGPIN-2016-03808
• 负责人: Mandl, Judith
• 金额: $ 2.62万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614641
• 关键词: Linking; cell; receptor; sequence; function

T cells are critical effector cells of the adaptive immune system which recognize foreign antigen in the form of peptides presented by host cell major histocompatibility complexes (MHC). Each T cell bears a unique antigen recognition receptor, the T cell receptor (TCR), which determines the exquisite specificity and the affinity with which an individual T cell binds peptide-MHC. The TCR is generated through rearrangement of germline encoded gene segments and the addition of non-templated (non-germline encoded) nucleotides by an enzyme called terminal deoxynucleotidyl transferase (TdT). The interaction strength between the TCR and peptide-MHC is a critical parameter in all T cell fate decisions, from selection in the thymus during development to differentiation during infection. Yet, due to the enormous diversity of TCRs that can be made (>1015 distinct receptors), predicting functional characteristics of a T cell from its TCR sequence is an unsolved challenge. Moreover, while the enormous TCR diversity within a T cell repertoire that is added by TdT during TCR gene segment rearrangement is thought to be essential in effective host protection, this has not been demonstrated experimentally. Thus, the link between TCR sequence diversity, pMHC binding strength, and T cell function in host protection remains unclear. To date, it has been difficult to discern global patterns in TCR sequence or binding affinity for a T cell population without prior knowledge of the range of peptide-MHC ligands for each TCR. To overcome this limitation, we propose a novel approach that interrogates the impact of the TCR sequence on T cell function in an unbiased manner. We previously described that T cell expression of the membrane protein CD5 is directly proportional to the strength of the TCR signal obtained from self-ligands as well as foreign antigens presented in the context of MHC. Thus, by sorting CD4 T cells into CD5hi and CD5lo populations, we can now investigate properties of TCR sequences with distinct binding strengths for peptide-MHC without requiring prior knowledge of the peptides that they recognize. We hypothesize that CD5hi cells contain predominantly germline-encoded TCRs that are evolutionarily conserved to bind foreign peptide-MHC that we frequently encounter as a species. In contrast, we predict that CD5lo cells are enriched for TdT-dependent TCRs to provide the additional diversity that is required to respond to new and divergent pathogens. We will determine whether lower affinity TCRs that are generated by TdT-mediated junctional nucleotide additions play a fundamentally different role in the immune system than do high affinity TCRs. Overall, my research program will provide fundamental insight into the quantitative and qualitative features of an effective T cell repertoire and shed light on the evolutionary pressures that led to the use of TdT to increase TCR diversity.

T细胞是适应性免疫系统的关键效应细胞，它识别宿主细胞主要组织相容性复合体（MHC）以肽形式呈现的外来抗原。每个T细胞都有一个独特的抗原识别受体，即T细胞受体（TCR），它决定了单个T细胞与肽- mhc结合的特异性和亲和力。TCR是通过一种称为末端脱氧核苷酸转移酶（TdT）的酶对种系编码基因片段的重排和非模板（非种系编码）核苷酸的添加而产生的。TCR和肽- mhc之间的相互作用强度是所有T细胞命运决定的关键参数，从发育期间胸腺的选择到感染期间的分化。然而，由于可以制造的TCR具有巨大的多样性（bbb1015种不同的受体），从TCR序列预测T细胞的功能特征是一个尚未解决的挑战。此外，虽然TdT在TCR基因片段重排过程中增加的T细胞库中巨大的TCR多样性被认为对有效的宿主保护至关重要，但这尚未得到实验证明。因此，TCR序列多样性、pMHC结合强度和T细胞在宿主保护中的功能之间的联系尚不清楚。