Philippe Stock

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.

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.

Helminth Infection with Litomosoides sigmodontis Induces Regulatory T Cells and Inhibits Allergic Sensitization, Airway Inflammation, and Hyperreactivity in a Murine Asthma Model

Numerous epidemiological studies have shown an inverse correlation between helminth infections and the manifestation of atopic diseases, yet the immunological mechanisms governing this phenomenon are indistinct. We therefore investigated the effects of infection with the filarial parasite Litomosoides sigmodontis on allergen-induced immune reactions and airway disease in a murine model of asthma. Infection with L. sigmodontis suppressed all aspects of the asthmatic phenotype: Ag-specific Ig production, airway reactivity to inhaled methacholine, and pulmonary eosinophilia. Similarly, Ag-specific recall proliferation and overall Th2 cytokine (IL-4, IL-5, and IL-3) production were significantly reduced after L. sigmodontis infection. Analysis of splenic mononuclear cells and mediastinal lymph nodes revealed a significant increase in the numbers of T cells with a regulatory phenotype in infected and sensitized mice compared with sensitized controls. Additionally, surface and intracellular staining for TGF-β on splenic CD4+ T cells as well as Ag-specific TGF-β secretion by splenic mononuclear cells was increased in infected and sensitized animals. Administration of Abs blocking TGF-β or depleting regulatory T cells in infected animals before allergen sensitization and challenges reversed the suppressive effect with regard to airway hyperreactivity, but did not affect airway inflammation. Despite the dissociate results of the blocking experiments, these data point toward an induction of regulatory T cells and enhanced secretion of the immunomodulatory cytokine TGF-β as one principle mechanism. In conclusion, our data support the epidemiological evidence and enhance the immunological understanding concerning the impact of helminth infections on atopic diseases thus providing new insights for the development of future studies.

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.

CD8+ T cells regulate immune responses in a murine model of allergen‐induced sensitization and airway inflammation

The role of CD8+ T cells in the development of allergic airway disease is controversial. On the one hand, CD8+ T cells are known to inhibit the development of airway hyperreactivity (AHR) in murine models of asthma. In humans, IL‐10‐producing CD8+ T cells were shown to act as regulatory cells, inhibiting both proliferation and cytokine secretion of T cells. On the other hand, CD8+ T cells can promote IL‐5‐mediated eosinophilic airway inflammation and the development of AHR in animal models. To examine this, we investigated the role of CD8+ T cells during the induction of allergen‐induced AHR and demonstrated a protective effect of CD8+ T cells. Depletion of CD8+ T cells prior to the immunization led to increased Th2 responses and increased allergic airway disease. However, after development of AHR, CD8+ T cells that infiltrated the lungs secreted high levels of IL‐4, IL‐5 and IL‐10, but little IFN‐γ, whereas CD8+ T cells in the peribronchial lymph nodes or spleen produced high levels of IFN‐γ, but little or no Th2 cytokines. These data demonstrate protective effects of CD8+T cells against the induction of immune responses and show a functional diversity of CD8+ T cells in different compartments of sensitized mice.

ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival

The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4+ iNKT than on CD4− iNKT cells. Furthermore, the number of CD4+ iNKT cells was significantly lower in spleens and livers of ICOS−/− and ICOSL−/− mice, and the remaining iNKT cells in ICOS−/− mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient Jα18−/− mice. In addition, direct activation of iNKT cells with α-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS−/− mice. The failure of ICOS−/− iNKT cells to induce AHR was due in part to an inability of the ICOS−/− iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL−/− mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4+ iNKT cell function, homeostasis, and survival in the periphery.

Role of PD-L1 and PD-L2 in allergic diseases and asthma

To cite this article: Singh AK, Stock P, Akbari O. Role of PD‐L1 and PD‐L2 in allergic diseases and asthma. Allergy 2011; 66: 155–162.

Inhibition of the allergic response by regulatory T cells

Purpose of reviewAllergic diseases are caused by the overdevelopment of T-helper type 2 biased immune responses in susceptible individuals. A number of recent studies indicate that regulatory T cells play an important role in controlling such T-helper type 2 biased responses not only in animal models, but in humans as well, and these will be reviewed in this article. Recent findingsA family of regulatory cells appears to be involved in regulating allergies. Both naturally occurring CD4+CD25+ regulatory T cells and inducible forms of antigen-specific regulatory T cells, both expressing the transcription factor foxp3, have been shown to inhibit the inappropriate immune responses involved in allergic diseases. Impaired expansion of natural or adaptive regulatory T cells is hypothesized to lead to the development of allergy, and treatment to induce allergen-specific regulatory T cells could provide curative therapies for allergy and asthma. SummaryAllergen-specific regulatory T cells play an important role in controlling the development of allergy and asthma.

Mucosal Tolerance and Immunity: Regulating the Development of Allergic Disease and Asthma

Allergic diseases and asthma are characterized by eosinophilic inflammation induced by Th2 lymphocytes. However, the immunological events and the molecular and cellular mechanisms that protect against and regulate these pathological immune responses are poorly understood. In this review, we discuss the role of immunological tolerance, regulatory T cells, and dendritic cells (DCs) in these protective processes. In addition, we discuss factors like the maturation state of DCs, source and effect of Il-10 production as well as specific combinations of costimulatory molecules in the antigen-presenting cell: T cell synapse, which determine whether tolerance or immunity develops in the respiratory mucosa in response to inhaled allergen.