Eli and Edythe Broad Center of Regeneration Medicine Department of Surgery, University of California-San Francisco, CA 94143, USA.
Blood. 2013 May 30;121(22):4595-602. doi: 10.1182/blood-2012-10-463174. Epub 2013 Apr 22.
In utero hematopoietic cell transplantation (IUHCTx) is a promising method to induce donor-specific tolerance but the mechanisms of antigen presentation that educate host T cells and the relative importance of deletion vs regulation in this setting are unknown. We studied the roles of direct and indirect antigen presentation (mediated by donor- and host-derived antigen-presenting cells [APCs], respectively) in a mouse model of IUHCTx. We found that IUHCTx leads to precocious maturation of neonatal host dendritic cells (DCs) and that there is early differentiation of donor-derived DCs, even after transplantation of a stem cell source without mature APCs. We next performed allogeneic IUHCTx into donor-specific T-cell receptor transgenic mice and confirmed that both direct and indirect antigen presentation lead to clonal deletion of effector T cells in chimeras. Deletion did not persist when chimerism was lost. Importantly, although the percentage of regulatory T cells (Tregs) after IUHCTx increased, there was no expansion in Treg numbers. In wild-type mice, there was a similar deletion of effector cells without expansion of donor-specific Tregs. Thus, tolerance induction after IUHCTx depends on both direct and indirect antigen presentation and is secondary to thymic deletion, without de novo Treg induction.
在子宫内造血细胞移植（IUHCTx）是一种有前途的方法，可以诱导供体特异性耐受，但在这种情况下，抗原呈递的机制，教育宿主 T 细胞和删除与调节的相对重要性尚不清楚。我们研究了 IUHCTx 小鼠模型中直接和间接抗原呈递（分别由供体和宿主来源的抗原呈递细胞介导）的作用。我们发现 IUHCTx 导致新生宿主树突状细胞（DC）的早熟成熟，并且即使在移植没有成熟 APC 的干细胞来源后，也有供体来源的 DC 的早期分化。我们接下来进行了同种异体 IUHCTx 到供体特异性 T 细胞受体转基因小鼠，并证实直接和间接抗原呈递都导致嵌合体中效应 T 细胞的克隆删除。当嵌合性丧失时，删除不会持续存在。重要的是，尽管 IUHCTx 后调节性 T 细胞（Tregs）的百分比增加，但 Treg 数量没有增加。在野生型小鼠中，没有供体特异性 Tregs 的扩张，也有类似的效应细胞删除。因此，IUHCTx 后的耐受诱导既依赖于直接和间接的抗原呈递，又依赖于胸腺删除，而不是新的 Treg 诱导。
