Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Achieving alloantigen-specific transplant tolerance through ablation of interferon regulatory factor 4 in T cells
*Methods: 1. Irf4fl/flCD4-Cre recipients were first transplanted with BALB/c hearts and then transplanted with BALB/c and C3H skin allografts 30 days later. 2. We first transplanted BALB/c hearts into Irf4fl/flCd4-Cre mice and treated them with anti-PD-L1 and anti-CTLA-4 mAbs on days 0, 3, and 5 post-heart grafting. All heart allografts were acutely rejected within 8 days as previously described Recipients with rejected heart allografts were then transplanted again with skin allografts 30 days after heart grafting. 3. CD45.1+ B6 mice were adoptively transferred with either CD45.2+ WT TEa or CD45.2+ Irf4‒/‒ TEa cells on day -1, and transplanted with BALB/c hearts on day 0. Recipients transferred with Irf4‒/‒ TEa cells were further treated with rat IgG or anti-PD-L1 plus anti-CTLA-4 mAbs (P+C group) on days 0, 3, and 5. Adoptively transferred CD45.2+ TEa cells were isolated from splenocytes on day 6 by flow cytometry sorting. RNA was isolated and gene expression profiles were determined by microarray analysis.
*Results: 1. we showed that heart-transplanted mice with T cell-specific IRF4 deletion were tolerant to donor-specific antigens and accepted the subsequently transplanted donor-type but not third-party skin allografts. 2. Despite the rejection of the primary heart grafts in T cell-specific Irf4 knockout mice under immune checkpoint blockade, the establishment of donor-specific tolerance in these mice was unhindered. 3. By tracking alloantigen-specific CD4+ T cells in vivo, we revealed that checkpoint blockade restored the expression levels of the majority of wild-type T cell-expressed genes in Irf4-deficient T cells on day 6 post-heart grafting, indicating the initial reinvigoration of Irf4-deficeint T cells. Nevertheless, checkpoint blockade did not restore cell frequency, effector memory cell generation, and IFN-γ/TNF-α production of Irf4−/− TEa cells at day 30 post-heart grafting.
*Conclusions: Targeting IRF4 represents a potential therapeutic strategy for driving intrinsic T cell dysfunction and achieving alloantigen-specific transplant tolerance.
To cite this abstract in AMA style:Zhang H, Wu J, Zou D, Chen W. Ablation of Interferon Regulatory Factor 4 in T Cells Induces “Memory” of Transplant Tolerance That is Irreversible by Immune Checkpoint Blockade [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/ablation-of-interferon-regulatory-factor-4-in-t-cells-induces-memory-of-transplant-tolerance-that-is-irreversible-by-immune-checkpoint-blockade/. Accessed July 7, 2020.
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