Reply to Seth et al.: DNAX accessory molecule-1 (DNAM-1) plays an important role in alloreactive CD8 ⁺ T cells responsible for the exacerbation of acute graft-versus-host disease

Abstract

We appreciate the comments of Seth et al.(1), because they provide an important finding that is supplementary to our paper (2). They show that recipient mice deficient in CD155 (Cd155 −/− mice), a ligand for DNAM-1 (DNAX accessory molecule-1, CD226), exhibited shorter rather than longer survival than WT mice after bone marrow transplantation (BMT) with full MHC disparity. They also show that donor CD4 + , but not CD8 + , T cells were responsible for the poor survival of the recipient Cd155 −/− mice, suggesting that the interaction of CD155 on recipient organs with the receptor ligand on donor CD4 + T cells protects recipient mice from lethal disease after BMT. This observation does not necessarily contradict our findings that DNAM-1 on donor CD8 + T cells is involved in the exacerbation of acute graft-versus-host disease (GVHD) (2). Importantly, CD4 + T cells express TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is another receptor ligand for CD155 that mediates an inhibitory signal in T cells through interaction with CD155 on antigen-presenting cells (3). The binding affinity of TIGIT for CD155 is higher than that of DNAM-1 (3). Thus, one possible explanation for the findings of Seth et al. (1) is that CD4 + T cells might be led out of negative control by TIGIT, resulting in acceleration of alloreactive CD4 + T-cell priming and activation. As shown in our paper (2), DNAM-1 is involved in acute GVHD mediated by CD8 + , but not CD4 + , T cells.Therefore, this may be the reason why anti-DNAM-1 neutralizing antibody had no effect on the survival of Cd155

Increased CD112 Expression in Methylcholanthrene-Induced Tumors in CD155-Deficient Mice

“…We have previously shown that abrogating DNAM-1 activity on CD8+ T cells results in development of milder graft-versus-host disease (GVHD) [31] , [32] . On the other hand, Seth et al reported that the absence of CD155 aggravated acute GVHD, which is mainly caused by CD4 + T cells [33] .…”

Critical roles of co‐activation receptor DNAX accessory molecule‐1 in natural killer cell immunity

“…Co-stimulation of DNAM-1 induced the exacerbation of GVHD, while blocking DNAM-1 attenuated the effects of GVHD. 91,92 It remains to be seen whether DNAM-1 drives the anti-GVHD effects of NK cells in humans.…”

“…Using mouse models, the role of DNAM‐1 on the surface of CD8 + T cells in GVHD was determined. Co‐stimulation of DNAM‐1 induced the exacerbation of GVHD, while blocking DNAM‐1 attenuated the effects of GVHD . It remains to be seen whether DNAM‐1 drives the anti‐GVHD effects of NK cells in humans.…”