IL-6 Signalling to Responding T Cells Is Key to Calcitonin Gene-Related Peptide-Exposed Endothelial Cell Enhancement of Th17 Immunity During Langerhans Cell Antigen Presentation
Wanhong Ding
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorCameron Moattari
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorLori L. Stohl
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorJohn A. Wagner
Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorXi K. Zhou
Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorCorresponding Author
Richard D. Granstein
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Correspondence:
Richard D. Granstein ([email protected])
Search for more papers by this authorWanhong Ding
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorCameron Moattari
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorLori L. Stohl
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorJohn A. Wagner
Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorXi K. Zhou
Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, USA
Search for more papers by this authorCorresponding Author
Richard D. Granstein
Department of Dermatology, Weill Cornell Medicine, New York, New York, USA
Correspondence:
Richard D. Granstein ([email protected])
Search for more papers by this authorFunding: This work was supported by Filomen M. D'Agostino Foundation; Pfizer; National Center for Advancing Translational Sciences, UL1 TR002384; Seth Sprague Educational and Charitable Foundation.
ABSTRACT
Calcitonin gene-related peptide (CGRP) biases Langerhans cell (LC) Ag presentation to CD4+ T cells towards Th17-type immunity through actions on endothelial cells (ECs). We now report further evidence that IL-6 signalling at responding T cells mediates this effect. This CGRP effect was absent with ECs from IL-6 KO mice. Exposure of LCs, but not T cells, to IL-6 enhanced IL-6 and IL-17A production and reduced IFN-γ in the T-cell response. Pretreatment of LCs with IL-6 receptor α-chain (IL-6Rα) antibodies prior to IL-6 exposure significantly inhibited these responses. However, T-cell pretreatment with an IL-6/IL-6Rα chimera mimicked the effect of IL-6 pretreatment of LCs on T-cell responses. When this experiment was performed in the presence of the ADAM17 and ADAM10 inhibitor TAPI-1 during LC pretreatment of LCs and during the Ag presentation culture, release of soluble IL-6Rα chains into the medium was very significantly reduced, but this did not affect levels of T-cell cytokine release. Interestingly, LC exposure to IL-6 significantly increased LC IL-6 expression. Furthermore, pretreatment of T cells with antibodies against the IL-6 receptor β-chain significantly inhibited the IL-6 effect. CGRP may stimulate ECs in lymphatics and/or lymph nodes to produce IL-6 which likely results in migrating LCs nonclassically presenting IL-6. Furthermore, we found that IL-6 induces IL-6 production by LCs, suggesting an autocrine amplification pathway for this effect.
Conflicts of Interest
R.D. Granstein has a research agreement with Pfizer Inc. for a clinical study of calcitonin gene-related peptides. He is on the scientific advisory board of Elysium Health Inc. and holds equity and stock options; has research agreements with Galderma Inc., Leo Pharma Inc., Pfizer Inc., and Elysium Health Inc.; and is an advisor to Gore Range Capital and may receive fees for this. He is also an advisor to BelleTorus Corporation and holds stock options.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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