V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement.
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.
Sen
Yang
Y
Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, People's Republic of China.
Yongyi
Bi
B
Yuling
He
H
Luokun
Xie
X
Li
He
H
Jie
Xiong
X
Tao
Deng
D
Gang
Zhou
Z
Junyan
Liu
L
Chunsong
Hu
H
Zhang
Xuejun
X
Youxin
Jin
J
Feili
Gong
G
Boquan
Jin
J
Jinquan
Tan
T
D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054388:Receptors, CCR; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D000098862:T Lineage-Specific Activation Antigen 1
D000945:Antigens, Differentiation, T-Lymphocyte; C119309:CC chemokine receptor 9; D000098862:T Lineage-Specific Activation Antigen 1; D017252:CD3 Complex; D018925:Chemokines; D012333:RNA, Messenger; D054388:Receptors, CCR; D019707:Receptors, Chemokine