Vα24-Invariant NKT Cells from Patients with Allergic Asthma Express CCR9 at High Frequency and Induce Th2 Bias of CD3+ T Cells upon CD226 Engagement

Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, People's Republic of China.
The Journal of Immunology (Impact Factor: 4.92). 11/2005; 175(8):4914-26. DOI: 10.4049/jimmunol.175.8.4914
Source: PubMed


We have demonstrated that Valpha24(+)Vbeta11(+) invariant (Valpha24(+)i) NKT cells from patients with allergic asthma express CCR9 at high frequency. CCR9 ligand CCL25 induces chemotaxis of asthmatic Valpha24(+)i NKT cells but not the normal cells. A large number of CCR9-positive Valpha24(+)i NKT cells are found in asthmatic bronchi mucosa, where high levels of Th2 cytokines are detected. Asthmatic Valpha24(+)i NKT cells, themselves Th1 biased, induce CD3(+) T cells into an expression of Th2 cytokines (IL-4 and IL-13) in cell-cell contact manner in vitro. CD226 are overexpressed on asthmatic Valpha24(+)i NKT cells. CCL25/CCR9 ligation causes directly phosphorylation of CD226, indicating that CCL25/CCR9 signals can cross-talk with CD226 signals to activate Valpha24(+)i NKT cells. Prestimulation with immobilized CD226 mAb does not change ability of asthmatic Valpha24(+)i NKT cells to induce Th2-cytokine production, whereas soluble CD226 mAb or short hairpin RNA of CD226 inhibits Valpha24(+)i NKT cells to induce Th2-cytokine production by CD3(+) T cells, indicating that CD226 engagement is necessary for Valpha24(+)i NKT cells to induce Th2 bias of CD3(+) T cells. Our results are providing with direct evidence that aberration of CCR9 expression on asthmatic Valpha24(+)i NKT cells. CCL25 is first time shown promoting the recruitment of CCR9-expressing Valpha24(+)i NKT cells into the lung to promote other T cells to produce Th2 cytokines to establish and develop allergic asthma. Our findings provide evidence that abnormal asthmatic Valpha24(+)i NKT cells induce systemically and locally a Th2 bias in T cells that is at least partially critical for the pathogenesis of allergic asthma.

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    • "Unlike the T cells, unconventional glycolipid-reactive NKT cells that bridge innate and adaptive immunity set the keynote and the tone for the subsequent adaptive immune responses through expression of Th1/Th2 cytokines in response to glycolipid antigens. After activation, NKT cells rapidly produce Th1, Th2 cytokines and various chemokines, as well as up-regulate co-stimulatory molecules to respond to the infections, tumors and autoimmune disorders7, 10, 11, 12. Upon expression of CD4 and CD8 molecules, the NKT cells are divided into two main subpopulations including CD4+ and CD4− NKT cells, and the subpopulation of CD4− NKT cells is further subdivided into CD4−CD8− double negative (DN) and CD8+ single positive (SP) NKT cells, which is limited in human beings. It is widely believed that CD8 is expressed on a minor proportion of human NKT cells, but it is usually acquired after egression from the thymus13. "
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    ABSTRACT: Type capital I, Ukrainian natural killer T cells (NKT cells), a subset of CD1d-restricted T cells with invariant Valphabeta TCR, are characterized by prompt production of large amounts of Th1 and/or Th2 cytokines upon primary stimulation through the TCR complex. The rapid release of cytokines implies that type capital I, Ukrainian NKT cells may play a critical role in modulating the upcoming immune responses, such as anti-tumor response, protection against infection, and autoimmunity. As a bridge between innate and adaptive immunity, type capital I, Ukrainian NKT cells differentiate and mature upon stimulations to achieve and maintain a homeostasis. Orchestrating with other arms of adaptive immunity, type capital I, Ukrainian NKT cells show strong cytotoxic effects in response to various tumors in a direct and/or indirect manner(s). This review will focus primarily on type capital I, Ukrainian NKT cell development, homeostasis, and effector functions, especially in anti-tumor immunity, and followed by their potential applications in treatment of cancers.
    Acta Pharmacologica Sinica 09/2010; 31(9):1123-32. DOI:10.1038/aps.2010.119 · 2.91 Impact Factor
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    • "Our findings for NKT cell–macrophage behavior in mice and humans are distinct from previous reports of immune abnormalities in chronic inflammatory disease in general, and lung disease in particular. For example, iNKT cells were necessary for AHR in a mouse model of allergen-induced asthma and were found in increased numbers in allergic asthma patients (Akbari et al., 2003, 2006; Lisbonne et al., 2003; Sen et al., 2005). However, subsequent reports indicated that NKT cells were not necessary for airway inflammation in the mouse model and that the numbers of iNKT cells in BAL fluid or endobronchial biopsies were no different from normal in either asthma or COPD patients (Das et al., 2006; Vijayanand et al., 2007). "
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    ABSTRACT: To better understand the immune basis for chronic inflammatory lung disease, we analyzed a mouse model of lung disease that develops after respiratory viral infection. The disease that develops in this model is similar to asthma and chronic obstructive pulmonary disease (COPD) in humans and is manifested after the inciting virus has been cleared to trace levels. The model thereby mimics the relationship of paramyxoviral infection to the development of childhood asthma in humans. When the acute lung disease appears in this model (at 3 weeks after viral inoculation), it depends on an immune axis that is initiated by expression and activation of the high-affinity IgE receptor (FcvarepsilonRI) on conventional lung dendritic cells (cDCs) to recruit interleukin (IL)-13-producing CD4(+) T cells to the lower airways. However, when the chronic lung disease develops fully (at 7 weeks after inoculation), it is driven instead by an innate immune axis that relies on invariant natural killer T (iNKT) cells that are programmed to activate macrophages to produce IL-13. The interaction between iNKT cells and macrophages depends on contact between the semi-invariant Valpha14Jalpha18-TCR on lung iNKT cells and the oligomorphic MHC-like protein CD1d on macrophages as well as NKT cell production of IL-13 that binds to the IL-13 receptor (IL-13R) on the macrophage. This innate immune axis is also activated in the lungs of humans with severe asthma or COPD based on detection of increased numbers of iNKT cells and alternatively activated IL-13-producing macrophages in the lung. Together, the findings identify an adaptive immune response that mediates acute disease and an innate immune response that drives chronic inflammatory lung disease in experimental and clinical settings.
    Advances in Immunology 02/2009; 102:245-76. DOI:10.1016/S0065-2776(09)01205-X · 5.96 Impact Factor
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    • "Through cytokine production, they have the capacity to recruit secondary effector cells such as macrophages, basophils and eosinophils into the inflammatory zone where these cells become primed and subsequently activated for mediator secretion (Fig. 78.2). There has also been recent interest in the potential role of IL-4-and IL-13-secreting, CCR9 1 natural killer (NK) T cells in orchestrating the inflammatory response in chronic asthma (Sen et al. 2005; Akbari et al. 2006; Umetsu & Dekruyff 2006) (see Chapter 3) (Pham-Thi et al. 2006; Thomas et al. 2006), although initial findings of their primacy has been challenged (Ho 2007; Vijayanand et al. 2007). Overall, it is the Th2-type T cell bearing the CCR4 chemokine receptor that is the cell which dominates the allergic immune response and may be the cell most probably responsible for contributing to the ongoing chronic inflammatory response. "
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    ABSTRACT: While asthma is considered an inflammatory disorder of the conducting airways, it is becoming increasingly apparent that the disease is heterogeneous with respect to immunopathology, clinical phenotypes, response to therapies, and natural history. Once considered purely an allergic disorder dominated by Th2-type lymphocytes, IgE, mast cells, eosinophils, macrophages, and cytokines, the disease also involves local epithelial, mesenchymal, vascular and neurologic events that are involved in directing the Th2 phenotype to the lung and through aberrant injury-repair mechanisms to remodeling of the airway wall. Structural cells provide the necessary "soil" upon which the "seeds" of the inflammatory response are able to take root and maintain a chronic phenotype and upon which are superimposed acute and subacute episodes usually driven by environmental factors such as exposure to allergens, microorganisms, pollutants or caused by inadequate antiinflammatory treatment. Greater consideration of additional immunologic and inflammatory pathways are revealing new ways of intervening in the prevention and treatment of the disease. Thus increased focus on environmental factors beyond allergic exposure (such as virus infection, air pollution, and diet) are identifying targets in structural as well as immune and inflammatory cells at which to direct new interventions.
    Clinical & Experimental Allergy 07/2008; 38(6):872-97. DOI:10.1111/j.1365-2222.2008.02971.x · 4.77 Impact Factor
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