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 ROR{gamma}t transcription factor, in a TGF-{beta}1-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-{beta}1, 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.