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NOD 2/CARD 15和TLR 5中的“单核苷酸多态性”（SNP）的发生与异基因造血干细胞移植（HSCT）后患者的移植相关并发症之间的显著相关性。本研究的目的是在小鼠异基因骨髓移植模型中研究TLR 5对GVHD病程和严重程度的影响。此外，检查了TLR 5信号传导对过继转移的供体CD 4 + CD 25 + 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TLR 5缺乏使受体不易受GVHD的影响，如与TLR 5 +/+受体相比，其死亡率降低所证明的。相反，当与GVHD诱导的常规T细胞一起共移植到野生型受体中时，TLR 5 +/+和TLR 5-/-供体CD 4 + CD 25 + Treg细胞实现了类似的免于GVHD的保护。令人惊讶的是，我们检测到肠道植物群的改变的组成以及在具有其他健康外观的幼稚TLR 5-/-小鼠中自发的细菌移位至脾和肠系膜淋巴结，表明这些动物中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，TLR 5-/-小鼠被证明比TLR 5 +/+小鼠敏感得多，如在两种不同的感染模型中它们的死亡率增加所证明的。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.