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24-Invariant NKT Cells from Patients with Allergic Asthma Express CCR9 at High Frequency and Induce Th2 Bias of CD3+ T Cells upon CD226 Engagement1
,||,
* Department of Dermatology and
Department of Immunology, The First Affiliated Hospital, Anhui Medical University, Hefei, People’s Republic of China;
Department of Immunology,
Department of Public Health, and
¶ Department of Parasitology, Institute of Allergy and Immune-Related Diseases, Wuhan University School of Medicine and Public Health, Wuhan, People’s Republic of China;
|| The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, People’s Republic of China;
# Department of Internal Medicine, Renmin Hospital, Wuhan University, Wuhan, People’s Republic of China;
** Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; and
Department of Immunology, Fourth Military Medical University, Xian, People’s Republic of China
We have demonstrated that V
24+V
11+ invariant (V24+i) NKT cells from patients with allergic asthma express CCR9 at high frequency. CCR9 ligand CCL25 induces chemotaxis of asthmatic V24+i NKT cells but not the normal cells. A large number of CCR9-positive V24+i NKT cells are found in asthmatic bronchi mucosa, where high levels of Th2 cytokines are detected. Asthmatic V24+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 V24+i NKT cells. CCL25/CCR9 ligation causes directly phosphorylation of CD226, indicating that CCL25/CCR9 signals can cross-talk with CD226 signals to activate V24+i NKT cells. Prestimulation with immobilized CD226 mAb does not change ability of asthmatic V24+i NKT cells to induce Th2-cytokine production, whereas soluble CD226 mAb or short hairpin RNA of CD226 inhibits V24+i NKT cells to induce Th2-cytokine production by CD3+ T cells, indicating that CD226 engagement is necessary for V24+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 V24+i NKT cells. CCL25 is first time shown promoting the recruitment of CCR9-expressing V24+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 V24+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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