The NF-jB/Rel family member c-Rel was described to be required for the development of T H 1 responses. However, the role of c-Rel in the differentiation of T H 17 and regulatory CD41

Alterations of the airway microbiome are often associated with pulmonary diseases. For example, detection of the bacterial pathogen Moraxella catarrhalis in the upper airways is linked with an increased risk to develop or exacerbate asthma. However, the mechanisms by which M. catarrhalis augments allergic airway inflammation (AAI) remain unclear. We here characterized the cellular and soluble mediators of M. catarrhalis triggered excacerbation of AAI in wt and IL-17 deficient as well as in animals treated with TNF-α and IL-6 neutralizing antibodies. We compared the type of inflammatory response in M. catarrhalis infected, house dust mite (HDM)-allergic and animals infected with M. catarrhalis at different time points of HDM sensitization. We found that airway infection of mice with M. catarrhalis triggers a strong inflammatory response with massive neutrophilic infiltrates, high amounts of IL-6 and TNF-α and moderate levels of CD4+ T-cell-derived IFN-γ and IL-17. If bacterial infection occurred during HDM allergen sensitization, the allergic airway response was exacerbated, particularly by the expansion of Th17 cells and increased TNF-α levels. Neutralization of IL-17 or TNF-α but not IL-6 resulted in accelerated clearance of M. catarrhalis and effectively prevented infection-induced exacerbation of AAI. Taken together, our data demonstrate an essential role for TNF-α and IL-17 in infection-triggered exacerbation of AAI.

[5,6] and, most recently, Th9 cells producing 8]. All of these subsets differentiate from common precursor cells depending on * These authors contributed equally to this work.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3190 Hartmann Raifer et al. Eur. J. Immunol. 2012. 42: 3189-3201 the subset-driving cytokines during the first contact with the respective antigen. In this regard, IL-12 and IL-4 are considered to be the most important cytokines for generating Th1 or Th2 cells, respectively [9], while Th9 cells are raised in response to 8] and Th17 cells by 11]. Importantly, each of the Th subsets is also characterised by a lineagecharacterising transcription factor that is relevant for the generation and/or function of the respective subset. While T-bet and GATA3 characterise Th1 and Th2 cells, respectively [12,13], Th17 cells are dependent on RORγt and RORα [14,15], and Th9 cells require PU.1 and interferon regulatory factor 4 (IRF4) [16,17]. In contrast to conventional αβ T cells, γδ T cells form a TCR with γ and δ chains. These cells are part of the innate immune system, also produce cytokines such as IL-17 and IFN-γ and seem to produce these cytokines very rapidly [18]. Furthermore, unlike the relatively time-consuming processes that are necessary for Th-cell differentiation in the periphery as outlined above, γδ T cells are apparently pre-committed for cytokine production already in the thymus [19][20][21]. Within γδ T cells, IL-17 production correlates with a CCR6+ CD27 − phenotype [20,22,23] and the Vγ4 subset is particularly biased for IL-17 production [18]. Recently, a difference between αβ T cells and γδ T cells was also reported regarding the regulation of IL-17 production: the capacity to produce IL-17 directly ex vivo was strongly dependent on the NF-κB members RelA and RelB only in thymic γδ T cells but not in αβ T cells [24]. In contrast, thymic pre-commitment for IL-17-producing γδ T cells is suppressed by engagement of Skint-1, a thymic epithelial cell determinant [25]. With respect to function, IL-17-producing γδ T cells appear to form a major component of the defence against infections with bacteria such as Mycobacterium tuberculosis, Escherichia coli and pneumococci [26][27][28]. Likewise, IL-17-producing γδ T cells arise during autoimmune disorders such as rheumatoid arthritis or experimental autoimmune encephalomyelitis (EAE) [18,29,30]. We and others have studied the relevance of the interferon regulatory family of transcription factors for Th-cell differentiation. This family includes nine members (IRF1-9) in mammals that display gene homology and binding to relatively related motifs in the promoters of the genes they regulate [31]. Within interferon regulatory families, particularly IRF1, but to a lower degree also IRF2 and IRF8 are mandatory for Th1-cell differentiation [32]. In contrast, IRF4 has relatively pleiotropic roles by being absolutely required for Th2-and Th17-cell differentiation [33][34][35][36][37] and, as recently shown, for Th9-and T FH -cel...

Although it is generally accepted that dietary fiber is health promoting, the underlying immunological and molecular mechanisms are not well defined, especially with respect to cellulose, the most ubiquitous dietary fiber. Here, the impact of dietary cellulose on intestinal microbiota, immune responses and gene expression in health and disease was examined. Lack of dietary cellulose disrupted the age-related diversification of the intestinal microbiota, which subsequently remained in an immature state. Interestingly, one of the most affected microbial genera was Alistipes which is equipped with enzymes to degrade cellulose. Absence of cellulose changed the microbial metabolome, skewed intestinal immune responses toward inflammation, altered the gene expression of intestinal epithelial cells and mice showed increased sensitivity to colitis induction. In contrast, mice with a defined microbiota including A. finegoldii showed enhanced colonic expression of intestinal IL-22 and Reg3γ restoring intestinal barrier function. This study supports the epidemiological observations and adds a causal explanation for the health promoting effects of the most common biopolymer on earth.

The immunoproteasome subunit β5i has been shown to play an important role in Th1/Th17 driven models of colitis and arthritis. However, the function of β5i in Th2 dependent diseases remains enigmatic. To study the role of β5i in Th2-driven pathology, β5i knockout (KO) and control mice were tested in different models of experimental allergic asthma. β5i-deficient mice showed reduced OVA/Alum- and subcutaneous/OVA-induced acute asthma with decreased eosinophilia in the bronchoalveolar lavage (BAL), low OVA-specific IgG1 and reduced local and systemic Th2 cytokines. While Th2 cells in the lungs were reduced, Tregs and Th1 cells were not affected. Attenuated asthma in β5i KO mice could not be attributed to defects in OVA uptake or maturation of dendritic cells in the lung. Surprisingly, β5i deficient mice developed HDM asthma which was comparable to control mice. Here, we present novel evidence for the requirement of the β5i immunosubunit to generate a strong Th2 response during OVA- but not HDM-induced acute asthma. The unexpected role of β5i in OVA asthma remains to be clarified.