IL-27R-mediated regulation of IL-17 controls the development of respiratory syncytial virus-associated pathogenesis.

IL-27 is a heterodimeric cytokine composed of the subunits p28 and Epstein-Barr virus induced gene (EBI)-3 and is known for its effects on T-cell function and differentiation. IL-27 signals through the widely expressed IL-27 receptor (IL-27R), composed of the ligand-specific IL-27Rα chain and gp130. Engagement of the IL-27R activates STAT1 signaling, induces the expression of the type 1 helper T-cell (Th1) cytokine, interferon γ, and suppresses the differentiation of Th2 and Th17 cells.

House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection.

Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion.

Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection.

Recent work demonstrated the importance of macroautophagy in dendritic cell (DC) maturation and innate cytokine production upon viral infection through delivery of cytoplasmic viral components to intracellular TLRs. To study the functional consequences of impaired autophagosome formation during a respiratory syncytial virus (RSV) infection, mice harboring significant autophagy defects due to Beclin-1 haploinsufficiency (Beclin-1(+/-)) were used. Upon RSV infection in vivo, lungs of Beclin-1(+/-) mice showed increased Th2 cytokine production, mucus secretion, and lung infiltration of eosinophils and inflammatory DCs.

TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease.

Thymic stromal lymphopoietin (TSLP) has been implicated in the development of allergic inflammation by promoting Th2-type responses and has become a potential therapeutic target. Using in vitro T cell differentiation cultures we were able to validate that TSLP played a more critical role in the early development of Th2 immune responses with less significant enhancement of already developed Th2 responses. Adoptive transfer of naive DO11.

Respiratory syncytial virus infection modifies and accelerates pulmonary disease via DC activation and migration.

In the present studies, we have established that RSV can elicit a more pathogenic environment dependent on improper DC-associated sensitization. Our initial studies demonstrated that RSV, but not influenza, infection during an allergen exposure into the airway induced a more severe allergen response. The RSV-induced exacerbation included an increased Th2 cytokine response and pathophysiology as monitored by AHR and mucus overproduction.

Notch ligand delta-like 4 regulates development and pathogenesis of allergic airway responses by modulating IL-2 production and Th2 immunity.

Activation of the canonical Notch pathways has been implicated in Th cell differentiation, but the role of specific Notch ligands in Th2-mediated allergic airway responses has not been completely elucidated. In this study, we show that delta-like ligand 4 (Dll4) was upregulated on dendritic cells in response to cockroach allergen. Blocking Dll4 in vivo during either the primary or secondary response enhanced allergen-induced pathogenic consequences including airway hyperresponsiveness and mucus production via increased Th2 cytokines.

Distinct chemokine and cytokine gene expression pattern of murine dendritic cells and macrophages in response to Mycobacterium tuberculosis infection.

In this study, the early innate cytokine and chemokine response of murine dendritic cells (DCs) and macrophages to Mycobacterium tuberculosis infection was compared. The findings indicate a dissimilar gene expression pattern between the two cell types. The expression of IL-12 and IL-23, important for promoting Th1 and Th17 cells, respectively, was up-regulated only in DCs.

Nucleotide-binding oligomerization domain protein 2-deficient mice control infection with Mycobacterium tuberculosis.

Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. NOD2 has recently been shown to be important for host cell cytokine responses to Mycobacterium tuberculosis, to synergize with Toll-like receptor 2 (TLR2) in mediating these responses, and thus to serve as a nonredundant recognition receptor for M. tuberculosis.

Disparity in IL-12 release in dendritic cells and macrophages in response to Mycobacterium tuberculosis is due to use of distinct TLRs.

The control of IL-12 production from dendritic cells (DCs) and macrophages in response to Mycobacterium tuberculosis (Mtb) is not well understood. The objective of this study was to pursue the mechanism underlying our previous report that in response to Mtb infection, DCs release abundant IL-12, whereas secretion is limited in macrophages. An initial comparison of IL-12p35 and IL-12p40 gene induction showed that p35 transcription is similar in murine bone marrow-derived DCs and macrophages, but a rapid and enhanced IL-12p40 transcription occurs only in DCs.

Cbl-b differentially regulates activation-induced apoptosis in T helper 1 and T helper 2 cells.

We previously reported that ligation of CD3 induces antiapoptotic signals in T helper 2 (Th2) cells, and in contrast causes Th1 cells to undergo apoptosis. Here we show that Cbl-b is accountable for the unequal response, revealing a previously unknown cell-specific regulatory function for the molecule. Absence of Cbl-b resulted in resistance to activation-induced apoptosis in murine Th1 cells following CD3 ligation, akin to what is observed in Th2 cells containing Cbl-b.

IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition.

The initial TLR-mediated interaction between Mycobacterium tuberculosis and dendritic cells is critical, since the cytokine production that ensues can greatly influence the class of adaptive immunity that is generated to the pathogen. In this study, we therefore determined the dependency on TLR2 and TLR4 for M. tuberculosis-induced cytokine production by murine dendritic cells.

Lack of proapoptotic activity of soluble CD95 ligand is due to its failure to induce CD95 oligomers.

CD95 and CD95 ligand (CD95L) are critical molecules of the immune system. They play an important role in regulating T cell apoptosis. The membrane form of CD95L can be cleaved to release a soluble version, which possesses reduced apoptotic activity.

Signaling from cytokine receptors that affect TH1 responses.

Receptors of the various cytokines although structurally diverse, can yet be grouped into four major families of receptor proteins. Most cytokines that function in the immune system bind to either the Class I or Class II receptor families. Two other important receptor families are the immunoglobulin superfamily receptor and the TNF receptor family.