Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) may develop when donor-derived T cells recognize and damage genetically distinct normal host tissues. In addition to T cell receptor signaling, co-stimulatory pathways are involved in T cell activation. CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is expressed on APCs. The CD27/CD70 co-stimulatory pathway was shown to be critical for T cell function and survival in viral infection models. However, the role of this pathway in allo-HCT is previously unknown. In this study, we have examined its contribution in GVHD pathogenesis. Surprisingly, antibody blockade of CD70 following allo-HCT significantly increases GVHD. Interestingly, while donor T cell- or BM-derived CD70 plays no role in GVHD, host-derived CD70 inhibits GVHD as CD70-/- hosts show significantly increased GVHD. This is evidenced by reduced survival, more severe weight loss, and increased histopathologic damage compared to WT hosts. In addition, CD70-/- hosts have higher levels of proinflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-17. Moreover, accumulation of donor CD4+ and CD8+ effector T cells is increased in CD70-/- versus WT hosts. Mechanistic analyses suggest that CD70 expressed by host hematopoietic cells is involved in the control of alloreactive T cell apoptosis and expansion. Together, our findings demonstrate that host CD70 serves as a unique negative regulator of allogeneic T cell response by contributing to donor T cell apoptosis and inhibiting expansion of donor effector T cells.

T Cell–Derived CD70 Delivers an Immune Checkpoint Function in Inflammatory T Cell Responses

“…Meanwhile, we have confirmed this immune inhibitory function in both IBD and allogeneic GVHD models. Furthermore our recent publication shows that host-derived CD70 suppresses GVHD by limiting donor T cell expansion and effector function (34). Together our studies have demonstrated that T cell intrinsic CD70 signaling as well as CD27–CD70 interaction in both donor T cells and the host immune cells may contribute to the suppression of inflammatory T cell responses.…”

Co-stimulatory and co-inhibitory pathways in cancer immunotherapy

“…CD27 + and CD70 + cells often secrete higher levels of IFNɣ and are therefore more effective at inhibiting viral replication [220]. This is in contrast to studies looking at CD27 in the context of strong and persistent immune challenges, such as chronic infections or GVHD, where CD27-CD70 have been shown to play an inhibitory role on T cell responses [216,[223][224][225]. The role of CD27 in diseases is also dependent on tissue context and duration of expression [22].…”

Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs

“…The clinical GVHD manifestations are weight loss; change in posture, activity, fur texture, hair loss and in some cases diarrhea. Clinical GVHD is evaluated comprehensively with a scoring system as published before (17, 20).…”