Abstract
Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation. The mechanism involves the recognition of host antigens by donor-derived T cells which induces augmented response of alloreactive T cells. In this study, we characterized the role of a previously identified novel classical secretory protein with antitumor function-LYG1 (Lysozyme G-like 1), in aGVHD. LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio in vitro by MLR assay. By using major MHC mismatched aGVHD model, LYG1 deficiency in donor T cells or CD4+ T cells attenuated aGVHD severity, inhibited CD4+ T cells activation and IFN-γ expression, promoted FoxP3 expression, suppressed CXCL9 and CXCL10 expression, restrained allogeneic CD4+ T cells infiltrating in target organs. The function of LYG1 in aGVHD was also confirmed using haploidentical transplant model. Furthermore, administration of recombinant human LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production and inhibiting FoxP3 expression. The effect of rhLYG1 could partially be abrogated with the absence of IFN-γ. Furthermore, LYG1 deficiency in donor T cells preserved graft-versus-tumor response. In summary, our results indicate LYG1 regulates aGVHD by the alloreactivity of CD4+ T cells and the balance of Th1 and Treg differentiation of allogeneic CD4+ T cells, targeting LYG1 maybe a novel therapeutic strategy for preventing aGVHD.
Highlights
Acute graft-versus-host disease is medical complication which mainly destroy host tissues including the skin, liver, colon and the lung after allogeneic hematopoietic cell transplantation, representing a major cause for morbidity and non-relapse mortality [1, 2]
These results suggest that Lysozyme G-like 1 (LYG1) deficiency restrains the alloreactivity of CD4+ T cells in vitro
We found that the proportions of Regulatory T cells (Treg) cells (Foxp3+ gated on CD4+ T cells) in spleens were dramatically enhanced from recipients received Lyg1-/- donor T cells (Figure 3J), suggesting LYG1 deficiency in donor T cells promotes Treg differentiation
Summary
Acute graft-versus-host disease (aGVHD) is medical complication which mainly destroy host tissues including the skin, liver, colon and the lung after allogeneic hematopoietic cell transplantation (allo-HSCT), representing a major cause for morbidity and non-relapse mortality [1, 2]. Alloreactive T cells were the major detrimental factors during the pathogenesis of aGVHD [3, 4]. In GVHD, the donor T cells recognize the host antigens, activate, differentiate and traffic to the target organs under guidance of cytokines and chemokines, and result in inflammatory damages in the target organs [5]. IFN-g is a central regulatory cytokine in the initiation and maintenance of aGVHD due to its crucial function for CD4+ Th1 cells differentiation and CD8+ T cells function during the priming and expansion phase [6]. Regulatory T cells (Treg) which reduces the incidence and severity of aGVHD is one of the protective factors against aGVHD [7]. Due to the inhibitory characteristics, Treg cells have been widely studied for GVHD treatment in preclinical models and clinical trials [8, 9]
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