Influence of the pattern recognition receptor TLR5 on GVHD and the protective effect of donor CD4+CD25+ regulatory T cells following allogeneic bone marrow transplantation

我们最近证明了模式识别受体（PRR）基因NOD2/CARD15和TLR5中“单核苷酸多态性”（SNP）的发生与同种异体造血干细胞移植（HSCT）后患者的移植相关并发症之间存在显着关联。该项目的目的是在同种异体骨髓移植的小鼠模型中研究 TLR5 对 GVHD 病程和严重程度的影响。此外，还检查了 TLR5 信号传导对过继移植供体 CD4 CD25 Treg 细胞在 GVHD 中的保护作用的影响。第一个资助期的结果提供了证据，表明 TLR5 缺陷使受者不太容易受到 GVHD 的影响，与 TLR5/受者相比，他们的死亡率降低就证明了这一点。相比之下，当TLR5/和TLR5-/-供体CD4 CD25 Treg细胞与诱导GVHD的常规T细胞一起共移植到野生型受体中时，获得了类似的免受GVHD的保护。令人惊讶的是，我们在外观健康的幼稚 TLR5-/- 小鼠中检测到肠道菌群组成的改变以及自发的细菌易位至脾脏和肠系膜淋巴结，这表明这些动物对低但恒定的细菌负荷具有一定程度的耐受性。然而，在感染后，TLR5-/- 小鼠被证明比 TLR5/小鼠更敏感，这可以从两种不同感染模型中死亡率增加所证明。在第二个资助期，我们将研究这些令人惊讶的发现背后的细胞相互作用和分子过程。

We recently demonstrated a significant association between the occurrence of ‘single nucleotide polymorphisms’ (SNPs) in the pattern recognition receptor (PRR) genes NOD2/CARD15 and TLR5 and transplantation-related complications in patients following allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this project is to investigate the contribution of TLR5 to course and severity of GVHD in a murine model of allogeneic bone marrow transplantation. Furthermore, the influence of TLR5 signalling on the protective effect of adoptively transferred donor CD4+CD25+ Treg cells in GVHD is examined. Results of the first funding period provide evidence that TLR5 deficiency renders recipients less susceptible to GVHD, as demonstrated by their decreased mortality in comparison to TLR5+/+ recipients. In contrast, TLR5+/+ and TLR5-/- donor CD4+CD25+ Treg cells achieved a similar protection from GVHD when co-transplanted together with GVHD-inducing conventional T cells into wild type recipients. Surprisingly, we detected a modified composition of the intestinal flora as well as spontaneous bacterial translocation to spleen and mesenteric lymph nodes in naive TLR5-/- mice with otherwise healthy appearance, suggesting a certain degree of tolerance towards a low but constant bacterial burden in these animals. Upon infection, however, TLR5-/- mice proved to be much more sensitive than TLR5+/+ mice, as demonstrated by their increased mortality in two different infection models. In the second funding period we will examine the cellular interactions and molecular processes underlying these surprising findings.