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Host-Derived CD70 Suppresses Murine Graft-versus-Host Disease by Limiting Donor T
Cell Expansion and Effector Function
#MMPMID28550198
Leigh ND
; O'Neill RE
; Du W
; Chen C
; Qiu J
; Ashwell JD
; McCarthy PL
; Chen GL
; Cao X
J Immunol
2017[Jul]; 199
(1
): 336-347
PMID28550198
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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-?, IFN-?, 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.
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