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Calcineurin inhibitors suppress acute graft-vs-host disease via NFAT-independent inhibition of T cell receptor signaling
Shizuka Otsuka, … , Roberto Weigert, Jonathan D. Ashwell
Shizuka Otsuka, … , Roberto Weigert, Jonathan D. Ashwell
Published April 6, 2021
Citation Information: J Clin Invest. 2021. https://doi.org/10.1172/JCI147683.
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Research In-Press Preview Immunology

Calcineurin inhibitors suppress acute graft-vs-host disease via NFAT-independent inhibition of T cell receptor signaling

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Abstract

Inhibitors of calcineurin phosphatase activity (CNIs) such as cyclosporin A (CsA) are widely used to treat tissue transplant rejection and acute graft-versus-host disease (aGVHD), for which inhibition of NFAT-dependent gene expression is the mechanistic paradigm. We recently reported that CNIs inhibit TCR-proximal signaling by preventing calcineurin-mediated dephosphorylation of LckS59, an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we utilized T cells from mice that express LckS59A, which cannot accept a phosphate at residue 59, to initiate aGVHD. Although CsA inhibited NFAT-dependent gene upregulation in allo-aggressive T cells expressing either LckWT or LckS59A, it was ineffective in treating disease when the T cells expressed LckS59A. Two important NFAT-independent T cell functions were found to be CsA-resistant in LckS59A T cells: upregulation of the cytolytic protein perforin in tissue-infiltrating CD8+ T cells and antigen-specific T:DC (dendritic cell) adhesion and clustering in lymph nodes. These results demonstrate that effective treatment of aGVHD by CsA requires NFAT-independent inhibition of TCR signaling. Given that NFATs are widely expressed and off-target effects are a major limitation in CNI use, it is possible that targeting TCR-associated calcineurin directly may provide effective therapies with less toxicity.

Authors

Shizuka Otsuka, Nicolas Melis, Matthias M. Gaida, Debjani Dutta, Roberto Weigert, Jonathan D. Ashwell

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ISSN: 0021-9738 (print), 1558-8238 (online)

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