期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 12, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI150927
关键词
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资金
- NIH [R01AR073527, R01HL22489, R56AI139327, R37AI34495, R01HL56067, R01HL11879, T32CA082084, F30AI147437, S10OD011925, S10OD023402]
In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory antigen-presenting cells (APCs) secreting IL-12, which drives the response of donor Th1 cells, leading to graft-versus-host disease (GVHD). However, there are other mechanisms through which alloreactive T cell responses are initiated by directly acting on donor CD4(+) T cells. Among these mechanisms, fibroblastic reticular cell-derived DAMP IL-33 plays a critical role by enhancing T cell expansion and differentiation through the activation of T cell signaling pathways in response to alloantigen, resulting in GVHD.
Antigen-presenting cells (APCs) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory APCs that secrete IL-12, which is a driver of donor Th1 responses, causing graft-versus-host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cell responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD. We established that tissue damage signals are perceived directly by donor CD4(+) T cells and promoted T cell expansion and differentiation. Specifically, the fibroblastic reticular cell-derived DAMP IL-33 is increased by recipient conditioning and is critical for the initial activation, proliferation, and differentiation of alloreactive Th1 cells. IL-33 stimulation of CD4(+) T cells was not required for lymphopenia-induced expansion, however. IL-33 promoted IL-12-independent expression of Tbet and generation of Th1 cells that infiltrated GVHD target tissues. Mechanistically, IL-33 augmented CD4(+) T cell TCR-associated signaling pathways in response to alloantigen. This enhanced T cell expansion and Th1 polarization, but inhibited the expression of regulatory molecules such as IL-10 and Foxp3. These data establish an unappreciated role for IL-33 as a costimulatory signal for donor Th1 generation after alloHCT.
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