Cytokine mediators of chronic graft-versus-host disease
Kelli P.A. MacDonald, … , Bruce R. Blazar, Geoffrey R. Hill
Kelli P.A. MacDonald, … , Bruce R. Blazar, Geoffrey R. Hill
Published June 30, 2017
Citation Information: J Clin Invest. 2017;127(7):2452-2463. https://doi.org/10.1172/JCI90593.
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Review Series

Cytokine mediators of chronic graft-versus-host disease

Abstract

Substantial preclinical and clinical research into chronic graft-versus-host disease (cGVHD) has come to fruition in the last five years, generating a clear understanding of a complex cytokine-driven cellular network. cGVHD is mediated by naive T cells differentiating within IL-17–secreting T cell and follicular Th cell paradigms to generate IL-21 and IL-17A, which drive pathogenic germinal center (GC) B cell reactions and monocyte-macrophage differentiation, respectively. cGVHD pathogenesis includes thymic damage, impaired antigen presentation, and a failure in IL-2–dependent Treg homeostasis. Pathogenic GC B cell and macrophage reactions culminate in antibody formation and TGF-β secretion, respectively, leading to fibrosis. This new understanding permits the design of rational cytokine and intracellular signaling pathway–targeted therapeutics, reviewed herein.

Authors

Kelli P.A. MacDonald, Bruce R. Blazar, Geoffrey R. Hill

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Figure 1

Cytokines and signaling pathways associated with the effector populations of cGVHD.

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Cytokines and signaling pathways associated with the effector population...
(A) T effector cells respond to MHC/peptide on antigen presenting cells (APC) and, in the context of IL-6–, IL-23–, and IL-21–stimulated STAT3 phosphorylation, transcribe RORC to drive Th17 and Tc17 differentiation with secretion of IL-17 and related cytokines. IL-12 stimulation promotes T cell–specific T-box transcription factor (TBET) transcription and IFN secretion that signals in an autocrine fashion to enhance Th1 differentiation. Tbet expression and IFN-γ secretion are also characteristic of Th17/Tc17 cells after BMT. (B) Tregs respond to antigen within MHC class II and concurrent TGF-β and IL-2 signaling, which promotes STAT5 phosphorylation, SMAD signaling, and subsequent FOXP3 transcription. Immune regulation by secreted IL-10 and TGF-β ensues. (C) Tfh, identified by ICOS, CXCR5, and PD-1 expression, respond to antigen presented within MHC class II in the context of IL-6, IL-27, and IL-21 stimulation to drive STAT3 phosphorylation and BCL6 transcription, with subsequent secretion of IL-21. (D) BAFF and IL-21 drive GC B cell expansion and, in the context of B cell receptor signaling, subsequent SYK and BTK transcription promotes survival and allo- and autoantibody secretion. BLNK, B cell linker; NFAT, nuclear factor of activated T-cells; BCR, B cell receptor; PLC, phospholipase C.