The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Abstract

The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic cell death; it has potent antibacterial, antiviral and antifungal activity as well as being a powerful immunomodulator. It is released in proximity to CD4 + T cells during inflammatory and infectious disease but its impact on T cell phenotype is scarcely understood. Here we demonstrate that cathelicidin is a powerful Th17 potentiating factor which increases expression of the aryl hydrocarbon receptor (AHR) and the RORγt transcription factor, in a TGF-β1-dependent manner. We show that cathelicidin induces IL-17F production in particular, and that its induction of IL-17A+F+ double producing cells is dependent on AHR while its induction of IL-17F single producing cells is not. In the presence of TGF-β1, cathelicidin profoundly suppressed IL-2 and down-regulated T-bet, specifically directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1 cells were protected from apoptotic death by cathelicidin, in the first example of a neutrophil-released mediator inducing survival of a T cell subset. Finally, we show that cathelicidin is released by neutrophils in mouse lymph nodes following inoculation of heat-killed Salmonella typhimurium and that cathelicidin-deficient mice have suppressed Th17 responses during inflammation, but not at steady state. We propose that the release of cathelicidin by neutrophils is required for maximal Th17 differentiation and IL-17 production by CD4 + T cells, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses with some sophistication.

The Outcome of Neutrophil-T Cell Contact Differs Depending on Activation Status of Both Cell Types

“…The fact that they induce T cell activation and proliferation has not previously been demonstrated; however, our data supports work showing that individual intracellular neutrophil mediators can promote T cell differentiation and inflammatory cytokine production. For example, lactoferrin promotes Th1 generation in concert with BCG vaccination ( 44 ) and increases T cell cytokine production during infection with Staphylococcus aureus ( 45 ); the neutrophil alpha defensins induce NFkb signalling in T cells ( 46 ); and the granule peptide cathelicidin promotes Th17 differentiation ( 21 ) and activates CD8 + T cells ( 47 ). However, all of these interpretations must be made in light of the fact that NETotic neutrophils did not activate the T cells, but rather suppressed as significantly as resting cells.…”

“…An extra layer of complexity is provided by the fact that not only intact neutrophils, but also their released mediators, can affect T cell behavior. For example, exocytosis of certain anti-microbial and/or cytotoxic molecules such as myeloperoxidase and arginase-1 have been shown to suppress T cell proliferation ( 18 – 20 ), and we have recently shown that neutrophil-derived cathelicidin can skew T cell differentiation towards a Th17 phenotype and promote survival ( 21 ). Furthermore, release of neutrophil extracellular traps (NETs) can directly prime human CD4 + T cells by reducing their activation threshold so that they can respond to suboptimal stimulation ( 22 ).…”

“…However, MPO has been shown to be deposited in the lymph nodes 4 hours after OVA/LPS injection ( 32 ) and neutrophil cytoplasts (the remnants of NETs following the expulsion of their DNA) have been identified in the mediastinal lymph nodes of mice in a model of allergic asthma ( 2 ). Moreover, we have recently shown that neutrophil-derived cathelicidin can be observed in the lymph nodes of mice immunized with heat-killed Salmonella typhimurium ( 21 ).…”

Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma

“…In contrast, during asthma exacerbation, another work has found increased levels of IL-17A from nasal lining fluid and increased frequency of Th17 cells in peripheral blood of asthmatic patients (66,98). One of the characteristics of those who had virus-driven asthma exacerbation was high sputum neutrophils that have shown to skew the polarization of naïve T cells to Th17 cells via neutrophil antimicrobial peptide cathelicidin (155,156). A recent prospective study identified a causal relationship between circulating IL-6 and asthma exacerbations, which could be plausibly explained by IL-6-driven differentiation of naïve T cells into Th17 cells that trigger asthma exacerbation (157).…”

Antimicrobial peptides: Defending the mucosal epithelial barrier

“…These structures trap proximal microbes and use the bound AMPs to kill or prevent bacterial and fungal growth. Within viable resting cells, AMPs, including defensins and cathelicidins, typically localize in cytoplasmic granules [63][64][65][66] and calprotectin in the cytoplasm [67,68].…”