Sensitivity and Resistance to Regulation by IL-4 during Th17 Maturation

Cooney, Laura A.; Towery, Keara; Endres, Judith; Fox, David A.

doi:10.4049/jimmunol.1002860

Cited by 73 publications

(60 citation statements)

References 46 publications

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“…Because in vitro and in vivo studies have shown that the Th2 cytokines IL-4 and IL-13 downregulate Th17 cellular expression of IL-17A (14,(16)(17)(18) and because IL-17 signaling is critical for airway neutrophilia and bacterial clearance in response to K. pneumoniae (6), we hypothesized that (i) preexisting allergic airway inflammation decreases lung IL-17A expression in response to acute bacterial infection and (ii) decreased lung IL-17A expression results in impaired neutrophil recruitment to the airways, decreased lung bacterial clearance, and an increased lung bacterial burden. To test these hypotheses, we developed a model of preexisting allergic airway inflammation, induced by OVA sensitization and challenge, followed by acute lung bacterial infection with K. pneumoniae (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Characteristic features of this allergic asthma phenotype include goblet cell metaplasia and mucus hypersecretion, airway hyperreactivity, smooth muscle hyperplasia, and airway eosinophilia (13). We and others have previously shown that the Th2 cytokines IL-4 and IL-13 negatively regulate IL-17A expression by Th17 cells (14)(15)(16)(17)(18). However, the ability of IL-4 and IL-13 to impair IL-17-dependent antibacterial immunity in the lung is not known.…”

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confidence: 99%

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Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

et al. 2014

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f The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

et al. 2014

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“…Studies from our group and others have established that STAT6 negatively regulates IL-17A expression in Th17 cells (9)(10)(11)(12)(13). By extension, we hypothesized that STAT6 also inhibits innate ␥␦17 cell cytokine secretion.…”

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confidence: 83%

STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

et al. 2016

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A pproximately 50% of the intraepithelial lymphocyte population is composed of ␥␦ T cells, which constitute a critical first line of defense against bacterial and fungal pathogens (1). In contrast to adaptive ␣␤ T cells, ␥␦ T cells are capable of immediate cytokine release, providing an initial innate layer of protection at mucosal surfaces while influencing the development of subsequent adaptive responses (2, 3). ␥␦17 cells are a subset of ␥␦ T cells that produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to antibacterial and antifungal defense (4). ␥␦17 cells also produce high levels of IL-17A in various models of inflammation and autoimmunity, including experimental autoimmune encephalitis, ischemic brain injury, and psoriasis (2, 3, 5-7). While these data highlight the importance of understanding how ␥␦17 cell function is regulated, this process remains poorly understood.␥␦17 cell function is controlled by multiple immune cell populations and soluble molecules, particularly cytokines. Within 4 to 8 h in the presence of the inflammatory cytokines IL-23 and IL-1␤, ␥␦17 cells secrete IL-17A without the need for T cell receptor (TCR) engagement (2). ␥␦17 cells constitutively express IL-23 receptor (IL-23R) and IL-1R1, providing for an efficient mechanism to induce rapid effector cytokine production. A recent study showed that the serine/threonine kinase Sgk1 is a novel, critical regulator of IL-23R expression (8).Studies from our group and others have established that STAT6 negatively regulates IL-17A expression in Th17 cells (9-13). By extension, we hypothesized that STAT6 also inhibits innate ␥␦17 cell cytokine secretion. STAT6 is a transcription factor important for Th2 differentiation, inhibiting Th1 differentiation and activating the B cell response (14). IL-4 signals through both the type I IL-4 receptor (IL-4R), which consists of IL-4R␣ and the common ␥-chain, and the type II IL-4R, which consists of IL-4R␣ and IL-13R␣, while IL-13 signals through only the type II IL-4R (15, 16). IL-4 binds to the IL-4R␣ subunit and IL-13 binds to the IL-13R␣ subunit of the IL-4 heterodimer receptor with high affinity, leading to the phosphorylation of STAT6 (17,18). STAT6 is expressed at high levels in the settings of parasitic infections (19) and asthma, during which STAT6 induces Th2 differentiation, IgE antibody class switching, goblet cell metaplasia, alternative macrophage activation, mucus expression, and airway remodeling (20). Thus, STAT6 attenuation of ␥␦17 cell function may impair host defenses against bacterial and fungal infections in people with asthma or parasitic infections.We found that ␥␦17 cells expressed the type I IL-4R, and that IL-4 increased STAT6 phosphorylation in ␥␦17 cells. Furthermore, IL-4 signaling attenuated ␥␦17 cell production of IL-17A and IL-17F. IL-4 also decreased ␥␦17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 regulates ␥␦17 cell cytokine expression in vivo, we used a mouse model of Klebsiella pneumoniae lung infection in mice deficien...

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“…While IL-4 neutralization with antibodies promotes IL-17A production by CD4 + T cells, exogenous IL-4 suppresses IL-17A expression [19,20]. IL-4 also suppresses IL-17F production from recently committed Th17 cells in a STAT6-dependent manner [21]. The antagonistic role of IL-4 on IL-17 is further underlined by studies using transcription factor-deficient mice.…”

Section: Silencing Th17-dominated Skin Inflammation By Il-4mentioning

confidence: 99%