CD81Deficient Mice Hyperreactivity Is Diminished in Allergen-Induced Airway (original) (raw)
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CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells
The Journal of Immunology, 2007
CD4 ؉ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4 ؉ and CD8 ؉ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8 ؉ T cells expressing the transgene for the OVA 257-264 peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4 ؉ IL-4 ؉ T cells but not CD4 ؉ IL-4 ؊ T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4 ؉ IL-4 ؉ T cells developed significant increases in the number of CD8 ؉ IL-13 ؉ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4 ؉ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8 ؉ T cells from OT-1 mice that received naive CD4 ؉ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8 ؉ T cells from OT-1 mice without CD4 ؉ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4 ؉ and CD8 ؉ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8 ؉ IL-13 ؉ T cell-dependent AHR and airway allergic inflammation.
Regulation of IgE production and airway reactivity by CD4−CD8− regulatory T cells
Immunobiology, 2015
The mechanisms of tolerance induction occurring in the course of allergen-specific immunotherapy have not been elucidated in full detail. Our study aimed to characterize high zone tolerance in mouse models of type I allergy and of allergic airway inflammation induced by subcutaneous sensitization of mice with high doses of the model allergen ovalbumin (OVA) without the use of adjuvant. Mice were immunized by subcutaneous injection of high doses (HD) of OVA or, for comparison, low doses (LD) of OVA in saline. HD-mice showed lower specific IgE, but augmented IgG in sera than LD-mice. Pre-treatment of mice with HD-OVA antigen-specifically inhibited IgE production subsequently induced by LD-OVA. OVA-restimulated splenocytes from HD-mice revealed hypoproliferation and impaired production of Th2-associated cytokines. HD-mice exhibited lower airway reactivity, goblet cell hyperplasia and mucus production, as well as IL-5 and IL-13 production in the lungs than LD-mice following local provocation. Recruitment of inflammatory cells into the airways was comparable, while the number of eosinophils in the bronchoalveolar lavage was substantially higher in HD-mice. Adoptive transfer of dnTC from HDmice into naïve mice, which were subsequently sensitized with LD-OVA, suppressed IgE production in the recipients. The number of dnTC was higher in the spleens of HD-mice than LD-mice. In conclusion, our study demonstrates that subcutaneous sensitization of mice with high doses of allergen in the absence of adjuvant results in attenuated airway reactivity as compared with LD-sensitization and induces CD4 − CD8 − dnTC with regulatory function on IgE production.
2000
Allergic airway inflammation and hyperreactivity are modulated by ␥␦ T cells, but different experimental parameters can influence the effects observed. For example, in sensitized C57BL/6 and BALB/c mice, transient depletion of all TCR-␦ ؉ cells just before airway challenge resulted in airway hyperresponsiveness (AHR), but caused hyporesponsiveness when initiated before i.p. sensitization. V␥4 ؉ ␥␦ T cells strongly suppressed AHR; their depletion relieved suppression when initiated before challenge, but not before sensitization, and they suppressed AHR when transferred before challenge into sensitized TCR-V␥4 ؊/؊ /6 ؊/؊ mice. In contrast, V␥1 ؉ ␥␦ T cells enhanced AHR and airway inflammation. In normal mice (C57BL/6 and BALB/c), enhancement of AHR was abrogated only when these cells were depleted before sensitization, but not before challenge, and with regard to airway inflammation, this effect was limited to C57BL/6 mice. However, V␥1 ؉ ␥␦ T cells enhanced AHR when transferred before challenge into sensitized B6.TCR-␦ ؊/؊ mice. In this study V␥1 ؉ cells also increased levels of Th2 cytokines in the airways and, to a lesser extent, lung eosinophil numbers. Thus, V␥4 ؉ cells suppress AHR, and V␥1 ؉ cells enhance AHR and airway inflammation under defined experimental conditions. These findings show how ␥␦ T cells can be both inhibitors and enhancers of AHR and airway inflammation, and they provide further support for the hypothesis that TCR expression and function cosegregate in ␥␦ T cells.
The Journal of Immunology, 2009
Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory ␥␦ T cells. The AHR-enhancing cells belong to the V␥1 ؉ ␥␦ T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR. However, unlike Th2 cells, the AHR enhancers arise in untreated mice, and we show here that they exhibit their functional bias already as thymocytes, at an HSA high maturational stage. In further contrast to Th2 cells and also unlike iNKT cells, they could not be stimulated to produce IL-4 and IL-13, consistent with their synergistic dependence on iNKT cells in mediating AHR. Mice deficient in IFN-␥, TNFRp75, or IL-4 did not produce these AHR-enhancing ␥␦ T cells, but in the absence of IFN-␥, spontaneous development of these cells was restored by adoptive transfer of IFN-␥-competent dendritic cells from untreated donors. The i.p. injection of OVA/aluminum hydroxide restored development of the AHR enhancers in all of the mutant strains, indicating that the enhancers still can be induced when they fail to develop spontaneously, and that they themselves need not express TNFRp75, IFN-␥, or IL-4 to exert their function. We conclude that both the development and the cytokine potential of the AHR-enhancing ␥␦ T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR.
CD4 + T Cells Can Induce Airway Hyperresponsiveness to Allergen Challenge in the Brown Norway Rat
American Journal of Respiratory and Critical Care Medicine, 1998
Airway hyperresponsiveness to inhalational challenge with methacholine (MCh) develops by 32 h after allergen challenge of actively sensitized BN rats. To test the hypothesis that CD4 ϩ T cells mediate allergen-induced hyperresponsiveness independent of IgE-mediated mechanisms, we administered CD4 ϩ T cells, CD8 ϩ T cells, and a mixture of CD4 ϩ and CD8 ϩ T cells (total T cells) isolated from the cervical lymph nodes of rats sensitized with ovalbumin (OA) to naive BN rats that underwent aerosol challenge with either OA or bovine serum albumin (BSA) 2 d later. Responsiveness to MCh was measured 2 d before transfer of T cells and 32 h after challenge with OA or BSA. Airway responsiveness increased significantly in recipients of CD4 ϩ T cells after OA challenge, but not in any other of the treatment groups. Analysis of bronchoalveolar lavage (BAL) cells for major basic protein expression by immunostaining showed eosinophilia in OA-challenged CD4 ϩ and total T-cell recipients. Cells retrieved by bronchoalveolar lavage showed increased expression of IL-5 mRNA (in situ hybridization) in CD4 ϩ T cell recipients after OA challenge compared with other groups. Interferon-␥ mRNA was expressed to the greatest extent in CD8 ϩ recipients, but it was elevated in both OA-and BSA-challenged animals. We conclude that CD4 ϩ T cells can induce airway hyperresponsiveness after inhalational challenge with allergen and this is associated with IL-5 production and eosinophilia. CD8 ϩ T cells may have a negative regulatory effect on responsiveness, possibly mediated by interferon-␥. Mishima H, Hojo M, Watanabe A, Hamid QA, Martin JG. CD4 ϩ T cells can induce airway hyperresponsiveness to allergen challenge in the Brown Norway rat.
International Immunology, 2003
IL-1 is a pro-in¯ammatory cytokine consisted of two molecular species, IL-1a and IL-1b, and the IL-1 receptor antagonist (IL-1Ra) is a natural inhibitor of both molecules. Although it is suggested that IL-1 potentiates immune responses mediated by T h 2 cells, the role of IL-1 in asthma still remains unclear. In this study, we demonstrate that the ovalbumin (OVA)-induced airway hypersensitivity response (AHR) in IL-1a/b-de®cient (IL-1a/b ±/±) mice was signi®cantly reduced from the levels seen in wild-type mice, whereas the responses seen in IL-1Ra ±/± mice were profoundly exacerbated, suggesting that IL-1 is required for T h 2 cell activation during AHR. OVA-speci®c T cell proliferation, IL-4 and IL-5 production by T cells, and IgG1 and IgE production by B cells in IL-1a/b ±/± mice were markedly reduced compared with these responses in wild-type mice; such responses were enhanced in IL-1Ra ±/± mice. Using IL-1a ±/± and IL-1b ±/± mice, we determined that both IL-1a and IL-1b are involved in this reaction. Both IgG1 and IgE levels were reduced in IL-1b ±/± mice, while only IgE levels were affected in IL-1a ±/± mice, indicating a functional difference between IL-1a and IL-1b. These observations indicate that IL-1 plays important roles in the development of AHR.