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- Title
Calcineurin inhibitors suppress acute graft-versus-host disease via NFAT-independent inhibition of T cell receptor signaling.
- Authors
Otsuka, Shizuka; Melis, Nicolas; Gaida, Matthias M.; Dutta, Debjani; Weigert, Roberto; Ashwell, Jonathan D.
- 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 gene expression dependent on nuclear factor of activated T cells (NFAT) 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 used 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 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.
- Subjects
PERFORINS; T cell receptors; GRAFT versus host disease; CYTOTOXIC T cells; ACUTE diseases; CELL communication; PROTEINS; RESEARCH; ANIMAL experimentation; RESEARCH methodology; CELL receptors; MEDICAL cooperation; EVALUATION research; CYCLOSPORINE; CELLULAR signal transduction; COMPARATIVE studies; IMMUNOSUPPRESSIVE agents; T cells; MICE; PHARMACODYNAMICS
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 11, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI147683