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

ArticleinThe Journal of Immunology 175(8):4914-26 · November 2005with39 Reads
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.
    • "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. "
    [Show abstract] [Hide abstract] 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.
    Article · Sep 2010
    • "However, some increase in CD4 + a-GalCer-loaded CD1d tetramer + cells was seen in the BAL of asthmatic children as compared to normal controls (Thi et al., 2006), and an increased percentage of Va24 + 6B11 + iNKT cells was seen in the BAL of adult asthmatics, as compared to peripheral blood (Thomas et al., 2007). Finally, another recent study demonstrated that CCR9 + Va24 + INF-g-producing iNKT cells isolated from the peripheral blood of asthmatics, but not normal controls, can direct Th2 cytokine generation from cocultured conventional CD3 + T cells in a manner dependent on CD226, a member of the Ig superfamily that mediates cell-cell adhesion (Sen et al., 2005 ). This same CCR9 + Va24 + IFN-g-producing iNKT cell population was found in the bronchial biopsies of asthmatics, but not normal controls, and was associated with upregulation of mucosal Th2 cytokine transcripts as well as the CCR9 ligand CCL25, suggesting a role for IFN-g-producing iNKT cell in bronchial asthma. "
    [Show abstract] [Hide abstract] ABSTRACT: Activated mast cells, eosinophils, and basophils infiltrate the airways of asthmatics as a result of an overexuberant T helper 2 (Th2) cell immune response that drives the production of IgE, primes mast cells and basophils, and promotes tissue eosinophilia and mast cell hyperplasia. Recent evidence demonstrates that these innate effectors can be activated outside of this classical Th2 cell paradigm and that they have additional roles in promoting the development of innate and adaptive pulmonary inflammation. There is also an appreciation for the role of airway epithelial cells in orchestrating allergic pulmonary inflammation. Emerging data from basic research highlight the involvement of many unique pathways in the inflammation triggered by complex native allergens and microbes at the airway mucosal surface. Here, we review the role of effector cells and airway epithelial cells in augmenting and, at times, bypassing traditional Th2 cell-mediated allergic inflammation.
    Full-text · Article · Sep 2009
    • "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., 2003Akbari et al., , 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). "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Feb 2009
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