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

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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.