LYG1 Deficiency Attenuates the Severity of Acute Graft-Versus-Host Disease Via Skewing T Cells Polarization Towards Treg Cells

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). As a complex immunopathology, aGVHD depends on the recognition of host antigens by donor T cells and induces augmented response of alloreactive T cells. Despite considerable achievements in the treatment of aGVHD, it remains a major clinical problem for the patients undergoing allo-HSCT. Therefore, it is necessary to further illustrate new mechanisms and develop novel therapeutic strategies of aGVHD. Previously we reported LYG1 (Lysozyme G-like 1) as a novel classical secretory protein promoted antitumor function of T cell. In this study, the role of LYG1 in aGVHD was investigated. Firstly, we examined whether LYG1 affected the alloreactivity of CD4+ T cells in vitro by MLR assay and discovered that LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio. Then we confirmed these observations using a major MHC mismatched aGVHD model by transferring T cells sorting from WT B6 or Lyg1-/- mice with bone marrow cells from WT B6 mice into lethally irradiated BALB/c mice. The alloreactive CD4+ T cells and the proportions of Th1 cells decreased whereas the proportions of Treg cells increased in spleens and livers in mice receiving Lyg1-/- T cells. LYG1-deficient T cells attenuated aGVHD severity, inhibited the expression of CXCL9 and CXCL10 and restrained CD4+ T cells infiltrating in livers. Furthermore, administration of recombinant LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production. More importantly, LYG1 deficiency did not affect GVT (graft-versus-tumor) effects. In summary, we demonstrate LYG1 regulates aGVHD via modulating the alloreactivity of CD4+ T cells and differentiation of Th1/Treg cells. Our study indicates that LYG1 may be a novel target in aGVHD by mitigating aGVHD without impairing GVT function. The therapeutic effect of targeting LYG1 is required in future investigations.

Funding

This study was supported by grant from The National Natural Science Foundation of China (NSFC) (Grant Number 81600144) and grant from Research Foundation of Peking University First Hospital.