Interleukin-29: Just an extra string in the bow of Th17 cells or a target for therapeutic exploitation?

In this issue, Witte and colleagues describe the ability of IL-29, a type III interferon, to induce keratinocyte expression of CXCL9, CXCL10 and CXCL11, three chemokines implicated in the trafficking of activated Th1 T cells into sites of inflammation [1]. Given that Th17 cells may be the principal source of IL-29, this finding both strengthens the role of Th17 cells in antiviral defenses and may help explain the mixed Th1/Th17 phenotype seen in psoriasis, a common inflammatory skin disease. Immune competence at the epithelial barriers of the gut, lungs and skin takes a concerted effort from the epithelial cells themselves, antibodies, complement, and both resident and infiltrating immune cells to be able to mount a timely response to a barrier breach and invasion by potentially pathogenic microbes. T cells fulfill a vital defensive role in the epithelia, with non-recirculating tissue resident memory T cells providing rapid specific immune protection against the pathogens most commonly encountered in barrier tissues, supported by innate immune cells and circulating T cells that can be called upon as needed [2, 3]. One trade-off of having a battalion of heavily armed T cells within the tissues is that loss of control or dysregulation of these cells can initiate and sustain chronic autoimmune and inflammatory diseases, such as Crohn’s disease, multiple sclerosis and psoriasis. Over the last decade, the contribution of Th17 cells has been recognized as a vital aspect of immunity at epithelial barriers [4]; however, Th17 cells and IL-17A have also been implicated in a number of their pathologies [5]. IL-17A is a potent inducer of antimicrobial protein and peptide expression by epithelia. In the skin, IL-17A works synergistically with several cytokines including IFN-γ [6] and TNF-α [7] to potently drive the induction of a range of antimicrobial peptides and proteins including S100A7, A8 and A9, the cathelicidin LL-37 and human β-defensins (HBD)-2, 3 and 4. Working in concert, these antimicrobial peptides provide a broad spectrum of antibacterial activity and have also been demonstrated to have efficacy against some viruses [8]. In addition to their antimicrobial activities, the defensins have roles in the regulation of both innate and acquired immunity. HBD-2, 3 and 4 induce pro-inflammatory cytokine expression (IL-6, CXCL10, CCL2, CCL5 and CCL20), and the migration and proliferation of keratinocytes, promot ing wound heal ing [9] . HBD-2 is a lso a chemoattractant for macrophages, mast cells, activated neutrophils, memory T cells and dendritic cells (DCs) [10]. The converse is also true: when used at a high enough concentration, chemokines like CCL20 have been shown to possess antimicrobial activities [11]. Plaque psoriasis is a common inflammatory disease of the skin, thought to be driven by Th1 and Th17 Tcells unleashing a Bcytokine storm^, inducing keratinocyte hyperproliferation and perturbed epidermal maturation, resulting in a compromised epidermal barrier characteristic of the disease [12]. Elevated expression of antibacterial peptides and proteins in lesional psoriasis skin is well established, with an extensive inflammatory cytokine milieu driving antimicrobial peptide expression [13], some of which are amongst the most highly upregulated molecules in lesional psoriatic skin [14]. IL-17A is also a potent inducer of an array of antiviral genes such as myxovirus resistance A (MX1) and oligoadenylate synthetases (OAS); thus, Th17 T cells have the potential to contribute to antiviral defenses at epithelial barriers. In addition to increased expression of antimicrobial peptides, antiviral * Andrew Johnston andjoh@med.umich.edu