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细胞是小鼠和人的先天类B细胞。它们在胎儿/新生儿时期出现 独立于骨髓(BM)来源的祖细胞的发育，后来产生 卵泡B-2细胞。本质上，我们认为B-1a和B-2(卵泡B细胞)已经进化 从而创造出提供日益复杂的免疫能力的B细胞层， 对于B-1a，包括诱导自我耐受。因此，我们在这里表明：1)B-1a表示高 Aire水平，它促进胸腺APC和APC表达/提呈自身抗原 从而促进T细胞耐受的诱导；2)新生儿B-1a活化和Aire的诱导 胸腺依赖于CD4+T细胞介导的CD40信号，并需要T细胞表达a 特辑；3)部分切除新生胸腺中的Foxp3+CD4+调节性T细胞 导致胸腺B-1a数量减少；反过来，4)胸腺B-1a细胞枯竭 在新生儿生活中减少Treg的产生。总而言之，这些发现表明，B-1a 新生儿胸腺中细胞与CD4+胸腺细胞相互作用产生串扰，激活B-1a 细胞分化为Aire+IgM-IgD-CD5+APC；以及，5)这些细胞依次参与 选择在诱导/维持自我耐受中起关键作用的新生儿Treg细胞(21-23)。 在早期的研究中，我们已经表明在B细胞缺陷的情况下T细胞对B细胞的耐受性受损 UMT小鼠，即uMT小鼠中的CD4+T细胞抑制成年uMT宿主的B细胞重建。多数 值得注意的是，我们发现，新生的µMT小鼠中的B-1a细胞条件下的CD4+T细胞能够 建立卵泡B细胞(24个)。此外，我们发现新生儿微粒细胞移植中Treg的产生 小鼠数量减少，最引人注目的是，来自正常新生小鼠的Treg细胞抑制了 微管移植的CD4+T细胞的抑制功能，因为这些细胞能够在微管移植宿主中重建B细胞 当与BM共转移时，来自µMT小鼠的Treg细胞的共同转移失败。 综上所述，这些发现导致我们提出B-1a细胞在诱导T细胞中发挥关键作用 新生儿胸腺对B细胞的耐受性，B-1a细胞与CD4+胸腺细胞相互作用， 内化表面Ig M，分化为Aire+Ig M-Ig D NegCD5+APC，然后选择一个群体 具有B细胞耐受性的新生儿Treg细胞。这里提出的研究将检验这一假设 并将阐明由B-1a诱导和调节的B细胞耐受诱导机制 新生儿胸腺中的Treg。因此，这项研究的发现将为我们揭示 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细胞功能在自身免疫性疾病中的作用的新见解。