CD155 Regulates Regulatory T Cell Population and Attenuates Acute Graft-Versus-Host Disease

The leukocyte adhesion molecule DNAM-1, also known as CD226, is constitutively expressed of most CD4⁺ T cells, CD8⁺ T cells and natural killer (NK) cells. The poliovirus receptor CD155, which is expressed on both hematopoietic and non-hematopoietic cells, is a ligand for DNAM-1 and TIGIT. Upon ligand binding, DNAM-1 mediates an activating signal in T cells and NK cells. TIGIT acts as a marker for regulatory T cell (Treg) subset and contributes to the Treg-mediated suppression. We have recently demonstrated a critical role of DNAM-1 on donor T cells in the development of acute GVHD in a mouse model (Nabekura, et al, PNAS, 2010, 2011). Recent reports also showed that DNAM-1 on donor cells promoted acute GVHD in a CD4⁺ T cell-dependent manner via the inhibition of donor Treg expansion. Here, we found total body irradiation upregulated CD155 expression on recipient’s dendritic cell. Therefore, we examined the role of CD155 expressed on host cells in the development of acute GVHD by using CD155-deficient mice.

Lethally irradiated CB6F1 wild type (WT) or Cd155^-/- mice were transplanted with 5 x 10⁶ bone marrow (BM) cells together with 2 x 10⁶ splenic T cells derived from C57BL/6 mice. Cd155^-/- recipient mice showed body weight loss significantly greater than did WT mice after transplantation (P < 0.05). Furthermore, Cd155^-/- mice showed significantly shorter survival than WT mice (P < 0.01). Similar results were obtained in an acute GVHD model (C57BL/6→BALB/c, P < 0.05). Further analyses revealed that Cd155^-/- recipient mice showed decreased donor-derived Treg cell population, compared with WT recipient mice (P < 0.01). Depletion of Treg cells from transplanted splenic T cells resulted in comparable body weight loss and mortality between WT and Cd155^-/- recipient mice after transplantation. These results suggest that host CD155 regulates the number of Treg cells and attenuated the development of acute GVHD.