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- W4313408003 abstract "Abstract In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) that generate pro-inflammatory antigen-presenting cells (APC) that secrete IL-12 to initiate donor Type 1 T helper (Th1) responses causing graft-vs-host-disease (GVHD). Yet, other mechanisms exist to initiate alloimmune responses, as recipients with disrupted APC PAMP/DAMP signaling or lacking IL-12 develop GVHD. We used IL-33 receptor, ST2, deficient B6 mice as T cell donors into BALB/c recipients to test the hypothesis that the DAMP IL-33 bypasses APC and acts directly on donor CD4+ T cells to mediate early alloreactive T cells activation and differentiation. In our model, we transferred equal ratios of B6 Cd4-Cre x St2fl/fl (ST2ko) and Cd4-Cre (ST2wt) T cells into irradiated BALB/c recipients with and without IL-12 blockade. Donor T cells in the secondary lymphoid organs (SLOs) were characterized at days 1–3, 5, and 7 post alloHCT. We established that IL-33 DAMP functions involve the direct stimulation of donor CD4+ T cells, which promoted IL-12-independent Type 1 T helper cell (Th1) differentiation and expansion. We demonstrated that IL-33 is induced by recipient irradiation in PDPN+CD31− fibroblastic reticular cells (FRC) of the SLOs as early as 1 day post-radiation to increase alloreactive CD4+ T cell numbers. Mechanistically, IL-33 amplified CD4+ T cell TCR signaling in response to alloantigen to enhance Th1 cell activation and differentiation, while inhibiting regulatory molecule (i. e. IL-10 and Foxp3) expression. Thus, IL-33 is an unappreciated costimulatory signal in Th1 generation and a promising early target to prevent acute GVHD after alloHCT. Supported by NIH F30AI147437 and T32 CA082084 (GKD), NIH R01HL122489, R01AR073527, R56AI13927 (HRT)" @default.
- W4313408003 created "2023-01-06" @default.
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- W4313408003 date "2022-05-01" @default.
- W4313408003 modified "2023-09-27" @default.
- W4313408003 title "IL-33 upregulated in fibroblastic reticular cells after recipient conditioning acts as a novel costimulatory signal in the generation of alloreactive Type 1 T helper cells" @default.
- W4313408003 doi "https://doi.org/10.4049/jimmunol.208.supp.175.08" @default.
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