Omid Akbari

Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen

Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperreactivity and asthma. However, the specific mechanisms by which tolerance is induced by respiratory allergen are not clear. We report here that pulmonary dendritic cells (DCs) from mice exposed to respiratory antigen transiently produced interleukin 10 (IL-10). These phenotypically mature pulmonary DCs, which were B-7hi as well as producing IL-10, stimulated the development of CD4+ T regulatory 1–like cells that also produced high amounts of IL-10. In addition, adoptive transfer of pulmonary DCs from IL-10+/+, but not IL-10−/−, mice exposed to respiratory antigen induced antigen-specific unresponsiveness in recipient mice. These studies show that IL-10 production by DCs is critical for the induction of tolerance, and that phenotypically mature pulmonary DCs mediate tolerance induced by respiratory exposure to antigen.

Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity.

Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (TR) cells can mediate this protective effect. Mature pulmonary dendritic cells in the bronchial lymph nodes of mice exposed to respiratory allergen induced the development of TR cells, in a process that required T-cell costimulation via the inducible costimulator (ICOS)–ICOS-ligand pathway. The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice,* TR cells blocked the development of AHR. Both the development and the inhibitory function of regulatory cells were dependent on the presence of IL-10 and on ICOS–ICOS-ligand interactions. These studies demonstrate that TR cells and the ICOS–ICOS-ligand signaling pathway are critically involved in respiratory tolerance and in downregulating pulmonary inflammation in asthma.*There was an error in the AOP version of this article. The sentence in the abstract that read The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mouse TR cells, blocked the development of AHR was worded incorrectly. The following sentence is correct: The TR cells produced IL-10, and had potent inhibitory activity; when adoptively transferred into sensitized mice, TR cells blocked the development of AHR. This has been corrected in the HTML and the PDF. We regret this error.

Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity

Using natural killer T (NKT) cell–deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of Vα14i NKT cells. The failure of NKT cell–deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell–deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281−/− mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d−/− mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary Vα14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target Vα14i NKT cells may be clinically effective in limiting the development of AHR and asthma.

Asthma: an epidemic of dysregulated immunity

The remarkable increase in asthma prevalence that has occurred over the last two decades is thought to be caused by changes in the environment due to improved hygiene and fewer childhood infections. However, the specific infections that limit T helper type 2 (TH2)-biased inflammation and asthma are not fully known. Infectious organisms, including commensal bacteria in the gastrointestinal tract and hepatitis A virus, may normally induce the development of regulatory T (TR) cells and protective immunity that limit airway inflammation and promote tolerance to respiratory allergens. In the absence of such infections, TH2 cells—which are developmentally related to TR cells—develop instead and coordinate the development of asthmatic inflammation.

Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family

To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity.

The range of regulatory T cell (TR cell) types that control immune responses is poorly understood. We describe here a population of TR cells that developed in vivo from naive CD4+CD25− T cells during a T helper type 1 (TH1)–polarized response, distinct from CD25+ TR cells. These antigen-specific TR cells were induced by CD8α+ DCs, produced both interleukin 10 and interferon-γ, and potently inhibited the development of airway hyper-reactivity. These TR cells expressed the transcription factors Foxp3 and T-bet, indicating that these TR cells are related to TH1 cells. Thus, adaptive TR cells are heterogeneous and comprise TH1-like TR cells as well as previously described TH2-like TR cells, which express Foxp3 and are induced during the development of respiratory tolerance by CD8α− DCs.

Regulatory T cells control the development of allergic disease and asthma.

The role of T(H)2 cells in the pathogenesis of allergy and asthma has been well described. However, the immunologic mechanisms that downmodulate and protect against the development of these disorders are poorly characterized. A spectrum of CD4+ T cells, including T(H)1 cells, T(H)3 cells, regulatory T cells, CD25+ T cells, and natural killer T cells might play a critical role in regulating these diseases and are discussed in this review.

Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments. Although the etiology of IPF is unknown, dysregulated TGF-β signaling has been implicated in its pathogenesis. Recent studies also suggest a central role for abnormal epithelial repair. In this study, we sought to elucidate the function of epithelial TGF-β signaling via TGF-β receptor II (TβRII) and its contribution to fibrosis by generating mice in which TβRII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as TβRIINkx2.1-cre mice, were used to determine the impact of TβRII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-β signaling in vitro and in a bleomycin-induced, TGF-β-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, TβRIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial TβRII in alveolar homeostasis. Absence of TβRII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-β. However, TβRIINkx2.1-cre mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis. To our knowledge, these findings are the first to demonstrate a specific role for TGF-β signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.

Induction of Airway Hyperreactivity by IL-25 Is Dependent on a Subset of Invariant NKT Cells Expressing IL-17RB

IL-25 has been shown to induce Th2 responses and airway hyperreactivity (AHR) in mice, but the mechanism of action is not understood and it is unclear which cells mediate this disease. In this study we show that the receptor for IL-25, IL-17RB, is highly expressed on a subset of naive and activated CD4+ invariant NKT (iNKT) cells, but not on activated T cells. IL-17RB+ iNKT cells produced large amounts of Th2 cytokines that were substantially increased by IL-25 stimulation. Furthermore, IL-17RB+ iNKT cells were capable of restoring AHR in iNKT cell-deficient mice, whereas IL-17RB− iNKT cells failed to reconstitute AHR and lung inflammation. Finally, IL-17RB+ iNKT cells were detected in the lungs of wild-type mice, and induction of AHR by intranasal administration of IL-25 was significantly impaired in iNKT cell-deficient mice. Overall, our data suggest a critical role for iNKT cells in IL-25-mediated AHR. These results may lead to novel therapeutic approaches to target IL-17RB+ iNKT cells for the treatment of allergic asthma.

PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions

Interactions of the inhibitory receptor programmed death-1 (PD-1) with its ligands, programmed death ligand (PD-L)1 and PD-L2, regulate T-cell activation and tolerance. In this study, we investigated the role of PD-L1 and PD-L2 in regulating invariant natural killer T (iNKT)-cell-mediated airway hyperreactivity (AHR) in a murine model of asthma. We found that the severity of AHR and airway inflammation is significantly greater in PD-L2−/− mice compared with wild-type mice after either ovalbumin (OVA) sensitization and challenge or administration of α-galactosylceramide (α-GalCer). iNKT cells from PD-L2−/− mice produced significantly more interleukin (IL)-4 than iNKT cells from control mice. Moreover, blockade of PD-L2 interactions of wild-type iNKT cells in vitro with monoclonal antibodies (mAbs) resulted in significantly enhanced levels of IL-4 production. In contrast, PD-L1−/− mice showed significantly reduced AHR and enhanced production of interferon-γ (IFN-γ) by iNKT cells. iNKT-deficient Jα18−/− mice reconstituted with iNKT cells from PD-L2−/− mice developed high levels of AHR, whereas mice reconstituted with iNKT cells from PD-L1−/− mice developed lower levels of AHR compared with control. As PD-L2 is not expressed on iNKT cells but rather is expressed on lung dendritic cells (DCs), in which its expression is upregulated by allergen challenge or IL-4, these findings suggest an important role of PD-L2 on lung DCs in modulating asthma pathogenesis. These studies also indicate that PD-L1 and PD-L2 have important but opposing roles in the regulation of AHR and iNKT-cell-mediated activation.