Calcineurin inhibitors target Lck activation in graft-versus-host disease.

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Date: June 1, 2021
From: Journal of Clinical Investigation(Vol. 131, Issue 11)
Publisher: American Society for Clinical Investigation
Document Type: Report
Length: 1,868 words
Lexile Measure: 1450L

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Abstract :

Calcineurin inhibitors (CNIs) such as cyclosporin A and FK506 are widely administered immunosuppressive drugs. Calcineurin relieves inhibitory phosphorylation from nuclear factor of activated T cells (NFAT) transcription factors downstream of T cell receptor engagement, resulting in their nuclear translocation and the production of cytokines, including IL-2, IFN-[gamma], and TNF-[alpha]. It was previously believed that CNIs downregulate immunity by reducing NFAT activation. However, work from Otsuka et al. in this issue of the JCI revealed a second mechanism by which CNIs suppress T cell function. The authors previously reported that calcineurin removes an inhibitory phosphate from the tyrosine kinase Lck at Ser59 (Lck-S59) and that this dephosphorylation positively regulates T cell activation. In the present work, the authors showed that inhibition of Lck-S59 dephosphorylation was essential for the CNI-mediated suppression of acute graft-versus-host disease (aGVHD). These findings have important implications for future approaches to the management of aGVHD, organ transplant rejection, and autoimmune disease.

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Gale Document Number: GALE|A664447479