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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: 5.36). 11/2005; 175(8):4914-26. DOI: 10.4049/jimmunol.175.8.4914
Source: PubMed

ABSTRACT 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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    • "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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    • "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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    • "Furthermore, immunohistochemistry and RT-PCR of endobronchial biopsies identified more CCR9 þ NKT cells in the submucosa of the asthmatic than in the normal subjects (Sen et al., 2005). CCR9 is widely recognized as a gut homing receptor, which is expressed on intraepithelial and lamina propria intestinal lymphocytes, and the authors suggest a role for CCR9 in NKT migration to the lung in asthma. "
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