Hadi Maazi

ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity.

Allergic asthma is caused by Th2-cell-type cytokines in response to allergen exposure. Type 2 innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that, along with Th2 cells, contribute to the pathogenesis of asthma by producing copious amounts of IL-5 and IL-13, which cause eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. ILC2s express ICOS, a T cell costimulatory molecule with a currently unknown function. Here we showed that a lack of ICOS on murine ILC2s and blocking the ICOS:ICOS-ligand interaction in human ILC2s reduced AHR and lung inflammation. ILC2s expressed both ICOS and ICOS-ligand, and the ICOS:ICOS-ligand interaction promoted cytokine production and survival in ILC2s through STAT5 signaling. Thus, ICOS:ICOS-ligand signaling pathway is critically involved in ILC2 function and homeostasis.

Type 2 innate lymphoid cell suppression by regulatory T cells attenuates airway hyperreactivity and requires inducible T-cell costimulator–inducible T-cell costimulator ligand interaction

Background: Atopic diseases, including asthma, exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T (Treg) cells and the emerging type 2 innate lymphoid cells (ILC2s). Although ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood. Objective: In the present study, for the first time, we evaluate how Treg cells interact with pulmonary ILC2s and control their function. Methods: ILC2s and Treg cells were evaluated by using in vitro suppression assays, cell‐contact assays, and gene expression panels. Also, human ILC2s and Treg cells were adoptively transferred into NOD SCID &ggr;C‐deficient mice, which were given isotype or anti–inducible T‐cell costimulator ligand (ICOSL) antibodies and then challenged with IL‐33 and assessed for airway hyperreactivity. Results: We show that induced Treg cells, but not natural Treg cells, effectively suppress the production of the ILC2‐driven proinflammatory cytokines IL‐5 and IL‐13 both in vitro and in vivo. Mechanistically, our data reveal the necessity of inducible T‐cell costimulator (ICOS)–ICOS ligand cell contact for Treg cell–mediated ILC2 suppression alongside the suppressive cytokines TGF‐&bgr; and IL‐10. Using a translational approach, we then demonstrate that human induced Treg cells suppress syngeneic human ILC2s through ICOSL to control airway inflammation in a humanized ILC2 mouse model. Conclusion: These findings suggest that peripheral expansion of induced Treg cells can serve as a promising therapeutic target against ILC2‐dependent asthma.

Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy

Allergen‐specific immunotherapy (SIT) has been used since 1911, yet its mechanism of action remains to be elucidated. There is evidence indicating that CD4+FOXP3+ regulatory T cells (Treg cells) are induced during SIT in allergic patients. However, the contribution of these cells to SIT has not been evaluated in vivo.

Suppression of Th2-Driven Airway Inflammation by Allergen Immunotherapy Is Independent of B Cell and Ig Responses in Mice

Allergen-specific immunotherapy (IT) uniquely renders long-term relief from allergic symptoms and is associated with elevated serum levels of allergen-specific IgG and IgA. The allergen-specific IgG response induced by IT treatment was shown to be critical for suppression of the immediate phase of the allergic response in mice, and this suppression was partially dependent on signaling through FcγRIIB. To investigate the relevance of the allergen-specific IgG responses for suppression of the Th2-driven late-phase allergic response, we performed IT in a mouse model of allergic asthma in the absence of FcγRIIB or FcγRI/FcγRIII signaling. We found that suppression of Th2 cell activity, allergic inflammation, and allergen-specific IgE responses is independent of FcγRIIB and FcγRI/FcγRIII signaling. Moreover, we show that the IT-induced allergen-specific systemic IgG or IgA responses and B cell function are dispensable for suppression of the late-phase allergic response by IT treatment. Finally, we found that the secretory mucosal IgA response also is not required for suppression of the Th2-driven allergic inflammation by IT. These data are in contrast to the suppression of the immediate phase of the allergic response, which is critically dependent on the induced allergen-specific serum IgG response. Hence, IT-induced suppression of the immediate and late phases of the allergic response is governed by divergent and independent mechanisms. Our data show that the IT-induced suppression of the Th2 cell-dependent late-phase allergic response is independent of the allergen-specific IgG and IgA responses that are associated with IT treatment.

Lack of autophagy induces steroid-resistant airway inflammation

BACKGROUND Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. OBJECTIVE We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma. METHODS We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients. RESULTS For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent. CONCLUSION Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.

Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma.

Role of plasmacytoid dendritic cell subsets in allergic asthma.

Plasmacytoid dendritic cells (pDCs) are major type‐I interferon‐producing cells that play important roles in antiviral immunity and tolerance induction. These cells share a common DC progenitor with conventional DCs, and Fms‐like tyrosine kinase‐3 ligand is essential for their development. Several subsets of pDCs have been identified to date including CCR9+, CD9+, and CD2+ pDCs. Recently, three subsets of pDCs were described, namely CD8α−β−, CD8α+β−, and CD8α+β+ subsets. Interestingly, CD8α+β− and CD8α+β+ but not CD8α−β− pDCs were shown to have tolerogenic effects in experimentally induced allergic asthma. These tolerogenic effects were shown to be mediated by the generation of FOXP3+ regulatory T cells through retinoic acid and the induction of retinaldehyde dehydrogenase enzymes. These newly described subsets of pDCs show high potentials for novel therapeutic approaches for the treatment of allergic diseases. In this review, we will address the new progress in our understanding of pDC biology with respect to allergic disease, in particular allergic asthma.

Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses

CD80 plays a critical role in stimulation of T cells and subsequent control of infection. To investigate the effect of CD80 on HSV-1 infection, we constructed a recombinant HSV-1 virus that expresses two copies of the CD80 gene in place of the latency associated transcript (LAT). This mutant virus (HSV-CD80) expressed high levels of CD80 and had similar virus replication kinetics as control viruses in rabbit skin cells. In contrast to parental virus, this CD80 expressing recombinant virus replicated efficiently in immature dendritic cells (DCs). Additionally, the susceptibility of immature DCs to HSV-CD80 infection was mediated by CD80 binding to PD-L1 on DCs. This interaction also contributed to a significant increase in T cell activation. Taken together, these results suggest that inclusion of CD80 as a vaccine adjuvant may promote increased vaccine efficacy by enhancing the immune response directly and also indirectly by targeting to DC.

Activated plasmacytoid dendritic cells regulate type 2 innate lymphoid cell–mediated airway hyperreactivity

Background: Allergic asthma is a prevalent inflammatory disease of the airways caused by dysregulated immune balance in the lungs with incompletely understood pathogenesis. The recently identified type 2 innate lymphoid cells (ILC2s) play significant roles in the pathogenesis of asthma. Although ILC2‐activating factors have been identified, the mechanisms that suppress ILC2s remain largely unknown. Plasmacytoid dendritic cells (pDCs) are important in antiviral immunity and in maintaining tolerance to inert antigens. Objective: We sought to address the role of pDCs in regulating ILC2 function and ILC2‐mediated airway hyperreactivity (AHR) and lung inflammation. Methods: We used several murine models, including BDCA‐2–diphtheria toxin receptor (DTR) transgenic and IFN‐&agr; receptor 1–deficient mice, as well as purified primary ILC2s, to reach our objective. We extended and validated our findings to human ILC2s. Results: We show that activation of pDCs through Toll‐like receptor 7/8 suppresses ILC2‐mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. We further show that pDCs suppress cytokine production and the proliferation rate while increasing the apoptosis rate of ILC2s through IFN‐&agr; production. Transcriptomic analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by IFN‐&agr;. Conclusion: Activation of pDCs alleviates AHR and airway inflammation by suppressing ILC2 function and survival. Our findings reveal a novel regulatory pathway in ILC2‐mediated pulmonary inflammation with important clinical implications.

Lack of PD-L1 Expression by iNKT Cells Improves the Course of Influenza A Infection

There is evidence indicating that invariant Natural Killer T (iNKT) cells play an important role in defense against influenza A virus (IAV). However, the effect of inhibitory receptor, programmed death-1 (PD-1), and its ligands, programmed death ligand (PD-L) 1 and 2 on iNKT cells in protection against IAV remains to be elucidated. Here we investigated the effects of these co-stimulatory molecules on iNKT cells in the response to influenza. We discovered that compare to the wild type, PD-L1 deficient mice show reduced sensitivity to IAV infection as evident by reduced weight loss, decreased pulmonary inflammation and cellular infiltration. In contrast, PD-L2 deficient mice showed augmented weight loss, pulmonary inflammation and cellular infiltration compare to the wild type mice after influenza infection. Adoptive transfer of iNKT cells from wild type, PD-L1 or PD-L2 deficient mice into iNKT cell deficient mice recapitulated these findings. Interestingly, in our transfer system PD-L1−/−-derived iNKT cells produced high levels of interferon-gamma whereas PD-L2−/−-derived iNKT cells produced high amounts of interleukin-4 and 13 suggesting a role for these cytokines in sensitivity to influenza. We identified that PD-L1 negatively regulates the frequency of iNKT cell subsets in the lungs of IAV infected mice. Altogether, these results demonstrate that lack of PD-L1 expression by iNKT cells reduces the sensitivity to IAV and that the presence of PD-L2 is important for dampening the deleterious inflammatory responses after IAV infection. Our findings potentially have clinical implications for developing new therapies for influenza.