This diagram outlines the key mechanisms by which calcineurin (Cn) inhibitors and mammalian target of rapamycin (mTOR) inhibitors inhibit T-cell activation.

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This diagram outlines the key mechanisms by which calcineurin (Cn) inhibitors and mammalian target of rapamycin (mTOR) inhibitors inhibit T-cell activation triggered by presentation of antigen via the T-cell receptor (TCR). The first step in antigen presentation involves presentation of a peptide that is bound within the peptide-binding groove of the major histocompatibility complex (MHC) class II molecule. This complex is then presented to the TCR. This causes transmembrane signaling that increases intracellular calcium concentrations. The liberated calcium, bound to calmodulin (calm), interacts with Cn, a calcium-dependent serine/threonine phosphatase that dephosphorylates nuclear factor of activated T cells (shown here as NFATc), and this causes NFAT to translocate to the nucleus. There it binds to other nuclear components of NFAT (shown here as NFATn). This complex regulates the transcription of many cytokine genes, shown in the diagram. Cyclosporine (CsA), tacrolimus (TCL), and pimecrolimus (PCL) diffuse freely into the cytoplasm of T cells and bind with their respective immunophilins. This drug/immunophilin complex binds to Cn and blocks its ability to dephosphorylate NFAT, and thereby inhibits the production of cytokines, chemokines, and growth factors [interleukin 2 (IL-2), IL-3, IL-4, tumor necrosis factor-α, interferon-γ, granulocyte-macrophage colony-stimulating factor, etc.] that would normally be induced after T-cell activation via the TCR. Sirolimus (SRL) has a more complex intracellular mechanism of action. Although SRL and everolimus (EVL) bind macrophilin-12 (also known as FKBP-12), the immunophilin of TCL and PCL, its mechanism of action does not appear to be mediated by Cn inhibition. mTOR inhibitors block cell kinases that would have a direct effect on the cell cycle by also an indirect effect in chemokine, cytokine, and growth factor synthesis. APC = antigen-presenting cell. Source: Chapter 233. Immunosuppressive and Immunomodulatory Drugs, Fitzpatrick's Dermatology in General Medicine, 8e Citation: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick's Dermatology in General Medicine, 8e; 2012 Available at: http://accessmedicine.mhmedical.com/DownloadImage.aspx?image=/data/Books/gold8/gold8_c233f002.png&sec=41169883&BookID=392&ChapterSecID=41138970&imagename= Accessed: December 29, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved