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

CD 5 + B-1a细胞是小鼠和人的先天性B样细胞，在胎儿/新生儿期出现。 独立于骨髓（BM）衍生的祖细胞的发育， 滤泡B-2细胞。从本质上讲，我们认为B-1a和B-2（滤泡B细胞）已经进化 依次产生B细胞层，其提供逐渐更复杂的免疫能力， 对于B-1a，包括诱导自身耐受性。因此，我们在这里显示：1）B-1a表达高水平的 Aire水平，其促进胸腺APC表达/呈递自身抗原， 因此促进T细胞耐受的诱导; 2）新生儿中B-1 a活化和Aire诱导 胸腺依赖于CD 4 + T细胞介导的CD 40信号传导，并需要T细胞表达 特异性库; 3）新生儿胸腺中Foxp 3 + CD 4+调节性T（Treg）细胞的部分消融 导致胸腺B-1a数量减少;和，4）胸腺B-1a细胞耗竭 减少Treg的生成。总之，这些发现表明，B-1a 细胞与新生儿胸腺中的CD 4+胸腺细胞相互作用，产生激活B-1 a的串扰 细胞分化为Aire+ IgMIPs IgDIPs CD 5 + APC;和，5）这些细胞进而参与Aire + IgMIPs CD 5 + APC。 选择在诱导/维持自身耐受性中起关键作用的新生Treg细胞（21-23）。 在早期的研究中，我们已经表明，T细胞对B细胞的耐受性在B细胞缺陷型中受损。 µMT小鼠，即，µMT小鼠中的CD 4 + T细胞抑制成年µMT宿主中的B细胞重建。最 值得注意是，我们发现新生µMT小鼠中的B-1a细胞调节CD 4 + T细胞， 滤泡B细胞的建立（24）。此外，我们发现新生儿µMT中Treg的产生 小鼠中的Treg细胞减少，并且最引人注目的是，来自正常新生小鼠的Treg细胞抑制了小鼠中的Treg细胞。 µMT CD 4 + 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细胞的共转移不能做到这一点。 综上所述，这些发现使我们提出B-1a细胞在诱导T细胞活化中起关键作用。 对新生儿胸腺中B细胞的耐受性，其中B-1a细胞与CD 4+胸腺细胞相互作用， 内化表面IgM，分化为Aire+ IgMlCD 5 + APC，然后选择群体 新生儿Treg细胞，赋予B细胞耐受性。这里提出的研究将检验这一假设 并将阐明B-1 a诱导的、受下列因素调节的B细胞耐受诱导机制： 新生儿胸腺Treg。因此，这项研究的结果将揭示基本的 机制，管理新生儿免疫自我耐受的诱导，并将提供 Aire介导的B-1a细胞功能导致的自身免疫性疾病的新见解。

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.