Calcineurin inhibitors suppress acute graft-versus-host disease via NFAT-independent inhibition of T cell receptor signaling
| Autor: | Jonathan D. Ashwell, Debjani Dutta, Matthias M Gaida, Roberto Weigert, Shizuka Otsuka, Nicolas Melis |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
T cell Calcineurin Inhibitors Receptors Antigen T-Cell Graft vs Host Disease chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Tacrolimus Mice 03 medical and health sciences 0302 clinical medicine Immune system Downregulation and upregulation Cyclosporin a medicine Animals Humans Mice Knockout NFATC Transcription Factors biology Chemistry Calcineurin hemic and immune systems NFAT General Medicine 030104 developmental biology medicine.anatomical_structure Perforin 030220 oncology & carcinogenesis Acute Disease Commentary Cyclosporine Cancer research biology.protein Immunosuppressive Agents CD8 Signal Transduction Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | 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 Lck(S59), an inhibitory modification, raising the possibility of another mechanism by which CNIs suppress immune responses. Here we used T cells from mice that express Lck(S59A), 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 Lck(WT) or Lck(S59A), it was ineffective in treating disease when the T cells expressed Lck(S59A). Two important NFAT-independent T cell functions were found to be CsA-resistant in Lck(S59A) 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|