| First Author | Leigh ND | Year | 2017 |
| Journal | J Immunol | Volume | 199 |
| Issue | 1 | Pages | 336-347 |
| PubMed ID | 28550198 | Mgi Jnum | J:251500 |
| Mgi Id | MGI:6099797 | Doi | 10.4049/jimmunol.1502181 |
| Citation | Leigh ND, et al. (2017) Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T Cell Expansion and Effector Function. J Immunol 199(1):336-347 |
| abstractText | 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 TCR signaling, costimulatory pathways are involved in T cell activation. CD27 is a TNFR family member expressed on T cells, and its ligand, CD70, is expressed on APCs. The CD27/CD70 costimulatory 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, Ab blockade of CD70 after allo-HCT significantly increases GVHD. Interestingly, whereas donor T cell- or bone marrow-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 with wild-type hosts. In addition, CD70(-/-) hosts have higher levels of proinflammatory cytokines TNF-alpha, IFN-gamma, IL-2, and IL-17. Moreover, accumulation of donor CD4(+) and CD8(+) effector T cells is increased in CD70(-/-) versus wild-type 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. |
