Journal Article

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Smith, Katie J., Melrose, Lauren, MacDonald, Andrew S., Minns, Danielle, Alessandrini, Virginia, Davidson, Donald J., Hardisty, Gareth, Gwyer Findlay, Emily, Jackson-Jones, Lucy

2021

Overview

The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1, cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses. Neutrophils secrete numerous immune effector molecules including cathelicidin which is associated with antimicrobial properties. Here the authors implicate neutrophil derived cathelicidin in modulation of CD4 T cell homoeostasis and the promotion of Th17 CD4 T cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/2 / 13/21 / 13/31 / 38 / 631/250/127/1213 / 631/250/1619/554/1898 / 631/250/2152/1566/2493 / 631/250/2504/223/1699 / 64/60 / Adaptive immunity / Animals / Antiinfectives and antibacterials / Antimicrobial agents / Antimicrobial Cationic Peptides - pharmacology / Antimicrobial peptides / Apoptosis / Aromatic compounds / Cathelicidins / CD4 antigen / Cell Differentiation - drug effects / Cells, Cultured / Differentiation / Enzyme-Linked Immunosorbent Assay / Female / Flow Cytometry / Granulation / Helper cells / Humanities and Social Sciences / Humans / Immunohistochemistry / Immunomodulation / Immunomodulators / Interleukin 2 / Leukocytes (neutrophilic) / Lymph nodes / Lymphocytes / Lymphocytes T / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Neutrophilia / Neutrophils / Neutrophils - cytology / Neutrophils - drug effects / Peptides / Phenotypes / Phosphorylation / Phosphorylation - genetics / Phosphorylation - physiology / Pore Forming Cytotoxic Proteins - pharmacology / Science / Science (multidisciplinary) / Smad2 protein / Smad2 Protein - genetics / Smad2 Protein - metabolism / Smad3 Protein - genetics / Smad3 Protein - metabolism / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Th1 Cells - cytology / Th1 Cells - drug effects / Th1 Cells - metabolism / Th17 Cells - cytology / Th17 Cells - drug effects / Th17 Cells - metabolism / Transforming growth factor-b1