SUMMARY The interleukin-17 (IL-17) family of cytokines phylogenetically pre-dates the evolution of T cells in jawed vertebrates, suggesting that the ontogeny of the Th17 cell lineage must have arisen to confer an evolutionary advantage to the host over innate sources of IL-17. Using a model of mucosal immunization with the encapsulated bacteria Klebsiella pneumoniae, B cells largely recognized polysaccharide capsular antigens, which limited protection to only the vaccine strain. In contrast, memory Th17 cells proliferated in response to conserved outer membrane proteins and conferred protection against several serotypes of K. pneumoniae, including the recently described multi-drug resistant New Dehli metallolactamase strain. Notably, this heterologous, clade specific protection was antibody-independent, demonstrating the Th17 cell lineage confers a host advantage by providing heterologous mucosal immunity independent of serotype specific antibody.

Summary Respiratory infections and diseases are among the leading causes of death worldwide, and effective treatments likely require manipulating the inflammatory response to pathogenic microbes or allergens. Here we review mechanisms controlling the production and functions of interleukin-17 (IL-17) and IL-22, cytokines that direct several aspects of lung immunity. Innate lymphocytes (γδT cells, natural killer cells, innate lymphoid cells) are the major source of IL-17 and IL-22 during acute infections, while CD4+ T-helper 17 (Th17) cells contribute to vaccine-induced immunity. The characterization of dendritic cell (DC) subsets has revealed their central roles in T-cell activation. CD11b+ DCs stimulated with bacteria or fungi secrete IL-1β and IL-23, potent inducers of IL-17 and IL-22. On the other hand, recognition of viruses by plasmacytoid DCs inhibits IL-1β and IL-23 release, increasing susceptibility to bacterial superinfections. IL-17 and IL-22 primarily act on the lung epithelium, inducing antimicrobial proteins and neutrophil chemoattractants. Recent studies found that stimulation of macrophages and DCs with IL-17 also contributes to anti-bacterial immunity, while IL-22 promotes epithelial proliferation and repair following injury. Chronic diseases such as asthma and chronic obstructive pulmonary disease have been associated with IL-17 and IL-22 responses directed against innocuous antigens. Future studies will evaluate the therapeutic efficacy of targeting the IL-17/IL-22 pathway in pulmonary inflammation.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema.

The intestine is a critical site of immune cell development that not only controls intestinal immunity but extra-intestinal immunity as well. Recent findings have highlighted important roles for gut microbiota in shaping lung inflammation. Here, we discuss interactions between the microbiota and immune system including T cells, protective effects of microbiota on lung infections, the role of diet in shaping the composition of gut micro-biota and susceptibility to asthma, epidemiologic evidence implicating antibiotic use and microbiota in asthma and clinical trials investigating probiotics as potential treatments for atopy and asthma. The systemic effects of gut microbiota are partially attributed to their generating metabolites including short chain fatty acids, which can suppress lung inflammation through the activation of G protein-coupled receptors. Thus, studying the interactions between microbiota and immune cells can lead to the identification of therapeutic targets for chronic lower respiratory diseases.

STAT3-mediated induction of Reg3γ enhances bacteriostatic and bactericidal activity to pulmonary Staphylococcus aureus.

The initial engagement of the T cell receptor (TCR) through interaction with cognate peptide-MHC is a requisite for T cell activation and confers antigen specificity. While this is a key event in T cell activation, the duration of these interactions may affect the proliferative capacity and differentiation of the activated cells. Here, we developed a system to evaluate the temporal requirements for antigenic stimulation during an immune response, in vivo. Using antibodies that target specific antigens in the context of MHC, we were able to manipulate the duration of antigen availability to both CD4 and CD8 T cells during an active infection. During the primary immune response, the magnitude of the CD4 and CD8 T cell response was dependent on the duration of antigen availability. Both CD4 and CD8 T cells required sustained antigenic stimulation for maximal expansion. Memory cell differentiation was also dependent on the duration of antigen exposure, albeit to a lesser extent. However, memory development did not correlate with the magnitude of the primary response, suggesting that the requirements for continued expansion of T cells and memory differentiation are distinct. Finally, a shortened period of antigen exposure was sufficient to achieve optimal expansion of both CD4 and CD8 T cells during a recall response. It was also revealed that limiting exposure to antigen late during the response may enhance the CD4 T cell memory pool. Collectively, these data indicated that antigen remains a critical component of the T cell response after the initial APC-T cell interaction.

Commensal microbiota are critical for the development of local immune responses. In this article, we show that gut microbiota can regulate CD4 T cell polarization during pulmonary fungal infections. Vancomycin drinking water significantly decreased lung Th17 cell numbers during acute infection, demonstrating that Gram-positive commensals contribute to systemic inflammation. We next tested a role for RegIIIγ, an IL-22–inducible antimicrobial protein with specificity for Gram-positive bacteria. Following infection, increased accumulation of Th17 cells in the lungs of RegIIIγ−/− and Il22−/− mice was associated with intestinal segmented filamentous bacteria (SFB) colonization. Although gastrointestinal delivery of rRegIIIγ decreased lung inflammatory gene expression and protected Il22−/− mice from weight loss during infection, it had no direct effect on SFB colonization, fungal clearance, or lung Th17 immunity. We further show that vancomycin only decreased lung IL-17 production in mice colonized with SFB. To determine the link between gut microbiota and lung immunity, serum-transfer experiments revealed that IL-1R ligands increase the accumulation of lung Th17 cells. These data suggest that intestinal microbiota, including SFB, can regulate pulmonary adaptive immune responses.

Th17 cells contribute to mucosal immunity by stimulating epithelial cells to induce antimicrobial peptides, granulopoiesis, neutrophil recruitment, and tissue repair. Recent studies have identified important roles for commensal microbiota and Ahr ligands in stabilizing Th17 gene expression in vivo, linking environmental cues to CD4 T cell polarization. Epigenetic changes that occur during the transition from naïve to effector Th17 cells increase the accessibility of il17a, il17f, and il22 loci to transcription factors. In addition, Th17 cells maintain the potential for expressing T-bet, Foxp3, or GATA-binding protein-3, explaining their plastic nature under various cytokine microenvironments. Although CD4 T cells are major sources of IL-17 and IL-22, innate cell populations, including γδ T cells, NK cells, and lymphoid tissue-inducer cells, are early sources of these cytokines during IL-23-driven responses. Epithelial cells and fibroblasts are important cellular targets for IL-17 in vivo; however, recent data suggest that macrophages and B cells are also stimulated directly by IL-17. Thus, Th17 cells interact with multiple populations to facilitate protection against intracellular and extracellular pathogens.