Journal Article

DKFZ-2024-00854

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells.

Wißfeld, J. (First author)DKFZ* ; Hering, M.DKFZ* ; ten Bosch, N.DKFZ* ; Cui, G. (Last author)DKFZ*

2024
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/eji.202350825

Abstract: Cyclosporin A is a well-established immunosuppressive drug used to treat or prevent graft-versus-host disease, the rejection of organ transplants, autoimmune disorders, and leukemia. It exerts its immunosuppressive effects by inhibiting calcineurin-mediated dephosphorylation of the nuclear factor of activated T cells (NFAT), thus preventing its nuclear entry and suppressing T cell activation. Here we report an unexpected immunostimulatory effect of cyclosporin A in activating the mammalian target of rapamycin complex 1 (mTORC1), a crucial metabolic hub required for T cell activation. Through screening a panel of tool compounds known to regulate mTORC1 activation, we found that cyclosporin A activated mTORC1 in CD8+ T cells in a 3-phosphoinositide-dependent protein kinase 1 (PDK1) and protein kinase B (PKB/AKT)-dependent manner. Mechanistically, cyclosporin A inhibited the calcineurin-mediated AKT dephosphorylation, thereby stabilizing mTORC1 signaling. Cyclosporin A synergized with mTORC1 pathway inhibitors, leading to potent suppression of proliferation and cytokine production in CD8+ T cells and an increase in the killing of acute T cell leukemia cells. Consequently, relying solely on CsA is insufficient to achieve optimal therapeutic outcomes. It is necessary to simultaneously target both the calcineurin-NFAT pathway and the mTORC1 pathway to maximize therapeutic efficacy.

Keyword(s): AKT ; CD8+ ; CsA ; Ribosomal protein S6 ; T cells ; mTOR

Note: #EA:D192#LA:D192# / 2024 Jul;54(7):e2350825 / HI-TRON

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Contributing Institute(s):

1. T-Zell-Metabolismus (D192)
2. KKE Dermatoonkologie (A370)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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