Impact of TCR-pMHC affinity on prostate-specific CD4+ T cell development and function

TCR-pMHC 亲和力对前列腺特异性 CD4 T 细胞发育和功能的影响

• 批准号: 10311518
• 负责人: Donald Miguel Rodriguez
• 金额: $ 5.12万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311518
• 关键词: Address; Affinity; Agonist; Antigens; Autoantigens; Autoimmunity; Automobile Driving; Biology; Bone Marrow; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cells; Chimera organism; Clonal Deletion; Clone Cells; Collaborations; Complex; Data; Development; Engineering; Epitopes; Exclusion; Exhibits; FOXP3 gene; Frequencies; Histocompatibility Antigens Class II; Human; Immune Tolerance; In Vitro; Individual; Infiltration; Investigation; Laboratories; Ligands; Malignant Neoplasms; Mediating; Modeling; Mus; Oncogenes; Outcome; Pattern; Peptide/MHC Complex; Peptides; Peripheral; Physiological; Prevention; Property; Prostate; Prostatic; Prostatic Neoplasms; Regulation; Regulatory T-Lymphocyte; Research; Role; Specificity; Stains; Suggestion; System; T cell receptor repertoire sequencing; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thymus Gland; Tissues; Transgenes; Tumor Antigens; Tumor Immunity; Work; autoreactive T cell; density; draining lymph node; experience; insight; interest; novel; receptor binding; recruit; stem; thymocyte; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Foxp3+ CD4+ regulatory T (Treg) cells are critical for the prevention of autoimmunity and the regulation of antitumor immunity, functioning in part by suppressing the activation and function of conventional T cells. Treg cells depend on T cell receptor (TCR) stimulation for many facets of their biology, including thymic development, peripheral differentiation, and suppressive function. In this regard, the affinity of TCR binding to self-peptides complexed with MHC class II molecules (self-pMHCII) is thought to be a primary determinant of Treg cell development and function. Existing models of thymic selection posit that intermediate TCR-pMHCII affinities – at the threshold between positive and negative selection – promote optimal thymic Treg (tTreg) development, allowing Treg cell clones to differentiate while also evading clonal deletion. In addition, it has been suggested that Treg cells may be more sensitive to self-pMHC-II ligand than Foxp3neg conventional CD4+ T (Tconv) cells of the same specificity, potentially contributing to Treg-mediated suppression in the periphery. However, these proposed principles largely stem from the study of CD4+ T cells reactive to transgene-expressed foreign model antigens. As the expression patterns, ligand densities, and TCR-pMHCII affinities of such engineered antigen systems may not reflect those of endogenous self-antigens, it remains unclear whether the predictions of the affinity model apply to Treg cell clones reactive to natural self-ligands. To address this question, we have identified a panel of CD4+ T cell clones exhibiting varying sensitivities to the same endogenous tissue-restricted antigen (TRA), Tcaf3646-658 (“C4” peptide). C4 is an unmodified I-Ab restricted prostatic self-peptide that drives the thymic differentiation of a canonical Treg cell clone, MJ23. In other work, we also demonstrated that monoclonal MJ23 Treg cells are highly enriched in oncogene-driven prostate tumors, indicating that the C4 peptide is a naturally occurring tumor-associated antigen. Our new data using C4/I-Ab tetramers demonstrate that, in prostate-tumor-bearing mice, C4-reactive Treg and Tconv cells coexist in the tumor-draining lymph nodes, yet only the former is detected within the tumor infiltrate. Whether TCR-pMHCII affinity contributes to Tconv cell exclusion from prostate tumors remains unclear. Thus, this proposal seeks to define the role of TCR- pMHCII affinity in the thymic and peripheral selection of CD4+ T cells reactive to the natural TRA and tumor- associated antigen C4. The studies in Aim 1 will provide the first evidence testing the "TCR affinity" model for T cell clones reactive to a natural self-peptide that directs tTreg cell differentiation, offering a unique opportunity to validate and/or upend existing paradigms of thymic selection. The studies in Aim 2 mice will yield unique mechanistic insights into the factors driving the peripheral selection of TRA-reactive Treg and Tconv cells, and the selective enrichment of the former into the tumor microenvironment. Collectively, this work will leverage a novel and physiologically relevant TCR-ligand system to understand the impact of TCR-pMHCII affinity on the fundamental mechanisms by which immune tolerance is established and enforced.

项目总结/摘要 Foxp 3 + CD 4+调节性T（Treg）细胞对于预防自身免疫和调节免疫应答是至关重要的。 抗肿瘤免疫，部分通过抑制常规T细胞的活化和功能发挥作用。Treg 细胞在其生物学的许多方面依赖于T细胞受体（TCR）刺激，包括胸腺发育， 外周分化和抑制功能。在这方面，TCR与自身肽结合的亲和性是恒定的。 与MHC II类分子复合的pMHCII（自身pMHCII）被认为是Treg细胞的主要决定因素 发展和功能。现有的胸腺选择模型表明，中间TCR-pMHCII亲和力- 在阳性和阴性选择之间的阈值-促进最佳胸腺Treg（tTreg）发育， 允许Treg细胞克隆分化，同时也避免克隆缺失。此外，有人建议， Treg细胞对自身pMHC-II配体可能比Foxp 3 neg常规CD 4 + T（Tconv）细胞更敏感。 相同的特异性，可能有助于外周Treg介导的抑制。但这些 提出的原则主要源于对转基因表达的外源模型的CD 4 + T细胞反应性的研究 抗原由于这种工程化抗原的表达模式、配体密度和TCR-pMHCII亲和力 系统可能不反映内源性自身抗原的系统，目前尚不清楚是否预测的内源性自身抗原的系统可能不反映内源性自身抗原的系统，目前尚不清楚是否预测的内源性自身抗原的系统可能不反映内源性自身抗原的系统。 亲和力模型适用于与天然自身配体反应性Treg细胞克隆。为了解决这个问题，我们有 鉴定了一组CD 4 + T细胞克隆，其对相同的内源性组织限制性抗原表现出不同的敏感性。 抗原（TRA），Tcaf 3646 -658（“C4”肽）。C4是一种未经修饰的I-Ab限制性前列腺自身肽， 典型Treg细胞克隆MJ 23的胸腺分化。在其他工作中，我们还证明， 单克隆MJ 23 Treg细胞在癌基因驱动的前列腺肿瘤中高度富集，表明C4 肽是天然存在的肿瘤相关抗原。我们使用C4/I-Ab四聚体的新数据表明， 在携带前列腺肿瘤的小鼠中，C4反应性Treg和Tconv细胞共存于肿瘤引流淋巴液中， 淋巴结，但只有前者被检测到的肿瘤浸润。TCR-pMHCII亲和力是否有助于 前列腺肿瘤中Tconv细胞的排除仍不清楚。因此，这项建议旨在界定技术合作区域的作用， pMHCII在对天然TRA和肿瘤-T细胞反应的CD 4 + T细胞的胸腺和外周选择中的亲和力 相关抗原C4。目标1中的研究将提供第一个证据来检验T细胞的“TCR亲和力”模型。 细胞克隆对指导tTreg细胞分化的天然自身肽具有反应性，提供了独特的机会， 验证和/或颠覆现有的胸腺选择范式。在Aim 2小鼠中的研究将产生独特的 对驱动TRA反应性Treg和Tconv细胞的外周选择的因素的机制见解，以及 前者选择性富集到肿瘤微环境中。总的来说，这项工作将利用 新的和生理学相关的TCR-配体系统，以了解TCR-pMHCII亲和力对细胞增殖的影响。 免疫耐受建立和实施的基本机制。