Aire-dependent thymic B-1a cells play a key role in neonatal tolerance induction

Aire 依赖性胸腺 B-1a 细胞在新生儿耐受诱导中发挥关键作用

• 批准号: 10660882
• 负责人: Leonore A. Herzenberg
• 金额: $ 39.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-21 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660882
• 关键词: Ablation; Adult; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigen-Presenting Cells; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B cell reconstitution; B-Lymphocytes; Birth; Bone Marrow; CD4 Positive T Lymphocytes; CD5 Antigens; CTLA4 gene; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Cues; Development; FOXP3 gene; Generations; Helper-Inducer T-Lymphocyte; Housekeeping; Immune; Immune Tolerance; Immunoglobulin M; Impairment; Invaded; Life; Maintenance; Mediating; Molecular; Mus; Neonatal; Peripheral; Phenotype; Play; Population; Proliferating; Regulatory T-Lymphocyte; Reporting; Role; SLAM protein; Self Tolerance; Signal Transduction; Spleen; Structure of germinal center of lymph node; Surface; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; TNFRSF6 gene; Testing; Thymus Gland; Tissues; autoreactivity; fetal; humoral immunity deficiency; immune self tolerance; inhibitor; insight; man; natural antibodies; neonatal mice; neonate; pathogen; progenitor; thymocyte

CD5+ B-1a cells are innate-like B cells in mouse and man. They emerge during fetal/neonatal development independent of the bone marrow (BM)-derived progenitors that later give rise to follicular B-2 cells. In essence, we see B-1a and B-2 (follicular B cell) as having evolved sequentially to create B cell layers that provide progressively more complex immune capabilities, including, for B-1a, the induction of self-tolerance. Thus, we show here that 1) B-1a express high levels of Aire, which promotes the expression/presentation of self-antigens by thymic APCs and hence promotes the induction of T cell tolerance; 2) B-1a activation and Aire induction in neonatal thymus depends on CD4+ T cell-mediated CD40 signaling, and requires T cells expressing a special repertoire; 3) Partial ablation of Foxp3+ CD4+ regulatory T (Treg) cells in neonatal thymus results in decreased numbers of thymic B-1a; and, reciprocally, 4) Depletion of thymic B-1a cells during neonatal life decreases Treg generation. Together, these findings demonstrate that B-1a cells interact with CD4+ thymocytes in neonatal thymus to generate cross talk that activates B-1a cells to differentiate to Aire+IgMnegIgDnegCD5+ APCs; and, 5) these cells in turn participate in the selection of neonatal Treg cells that play a key role in inducing/maintaining self-tolerance (21-23). In earlier studies, we have shown that T cell tolerance to B cells is impaired in B cell-deficient µMT mice, i.e., CD4+ T cells in µMT mice inhibit B cell reconstitution in adult µMT hosts. Most significantly, we find that B-1a cells in neonatal µMT mice condition CD4+ T cells to enable establishment of follicular B cells (24). Further, we find that Treg generation in neonatal µMT mice is decreased and, most strikingly, that Treg cells from normal neonatal mice suppress the inhibitory function of µMT CD4+ T cells, as these cells enable B cell reconstitution in µMT hosts when co-transferred with BM whereases co-transfer of Treg cells from µMT mice fails to do so. Taken together, these findings lead us to propose that B-1a cells play a key role in inducing T cell tolerance to B cells in neonatal thymus, where the B-1a cells interact with CD4+ thymocytes, internalize surface IgM, differentiate to Aire+IgMnegIgDnegCD5+ APCs, and then, select a population of neonatal Treg cells that confer B cell-tolerance. Studies proposed here will test this hypothesis and will clarify the B cell tolerance induction mechanism that is induced by B-1a and regulated by Treg in neonatal thymus. Findings from this study will thus shed key light on the fundamental mechanisms that governs the induction of neonatal immunological self-tolerance, and will offer new insights into the autoimmune diseases to which Aire-mediated B-1a cell function contributes.

CD5+ B-1a 细胞是小鼠和人类中的先天性 B 细胞，它们在胎儿/新生儿期间出现。 发育独立于骨髓（BM）来源的祖细胞，随后产生 本质上，我们看到 B-1a 和 B-2（滤泡 B 细胞）已经进化。 依次创建 B 细胞层，提供逐渐更复杂的免疫功能， 对于 B-1a，包括自我耐受的诱导，因此，我们在此表明​​ 1) B-1a 表达高。 Aire 水平，促进胸腺 APC 表达/呈递自身抗原， 2) 新生儿B-1a激活和Aire诱导 胸腺依赖于 CD4+ T 细胞介导的 CD40 信号传导，并且需要 T 细胞表达 特殊曲目；3) 新生儿胸腺中 Foxp3+ CD4+ 调节性 T (Treg) 细胞的部分消融 导致胸腺 B-1a 数量减少；并且，反过来，4) 胸腺 B-1a 细胞耗竭 总之，这些发现表明 B-1a 在新生儿生命期间会减少 Treg 的生成。 细胞与新生儿胸腺中的 CD4+ 胸腺细胞相互作用，产生激活 B-1a 的串扰 细胞分化为 Aire+IgMnegIgDnegCD5+ APC；并且，5) 这些细胞依次参与 选择在诱导/维持自我耐受方面发挥关键作用的新生儿 Treg 细胞 (21-23)。 在早期的研究中，我们发现 B 细胞缺陷时 T 细胞对 B 细胞的耐受性受损 µMT 小鼠，即 µMT 小鼠中的 CD4+ T 细胞抑制成年 µMT 宿主的 B 细胞重建。 值得注意的是，我们发现新生 µMT 小鼠中的 B-1a 细胞调节 CD4+ T 细胞，从而使 滤泡 B 细胞的建立 (24) 此外，我们发现新生儿 µMT 中存在 Treg 生成。 小鼠的 Treg 细胞减少，最引人注目的是，来自正常新生小鼠的 Treg 细胞抑制 µMT CD4+ T 细胞的抑制功能，因为这些细胞能够在 µMT 宿主中重建 B 细胞 当与 BM 共转移时，而来自 µMT 小鼠的 Treg 细胞共转移则失败。 总而言之，这些发现使我们提出 B-1a 细胞在诱导 T 细胞中发挥关键作用 对新生儿胸腺中 B 细胞的耐受性，其中 B-1a 细胞与 CD4+ 胸腺细胞相互作用， 内化表面 IgM，分化为 Aire+IgMnegIgDnegCD5+ APC，然后选择群体 赋予 B 细胞耐受性的新生儿 Treg 细胞的数量本文提出的研究将检验这一假设。 阐明由B-1a诱导并由B-1a调节的B细胞耐受诱导机制 因此，这项研究的结果将揭示新生儿胸腺中的 Treg 的基本原理。 控制新生儿免疫自我耐受诱导的机制，并将提供 对 Aire 介导的 B-1a 细胞功能所促成的自身免疫性疾病的新见解。