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

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.

CCL25 induces α4β7 integrin‐dependent migration of IL‐17+γδ T lymphocytes during an allergic reaction

“…In addition, CCR9 + NKT cells recovered from the peripheral blood of these patients migrated in vitro toward CCL25 [33]. Herein, we found that during allergic reaction, CCR9 + γδ T lymphocytes accumulated in mouse pleura, suggesting the involvement of CCR9/CCL25 in γδ T-cell migration and/or activation during allergy.…”

EBV-Induced Human CD8+ NKT Cells Synergise CD4+ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

“…The synergistic effect of EBVexposed thymic CD4 + and CD8 + NKT cells significantly suppressed EBV-associated malignancies and prolonging animal survival (15). In a semi-permeable transwell membrane co-culture system, which prevented direct cell-cell contact between syngeneic spleen CD3 + CD56 -CD161 -T cells and NKT cells (24), the NKT cells lost their ability to direct biased cytokine secretion by syngeneic T cells (data not shown), strongly suggesting that this NKT cell activity is cell-cell contact dependent.…”

“…All real time quantitative RT-PCR (Q-PCR) reactions were performed as described elsewhere (24). Briefly, total RNA from purified cells (1  10 4 , purity > 99%) or cell lines was prepared with the Quick Prep  total RNA extraction kit (Pharmacia Biotech) according to the manufacturer's instructions.…”

Type I natural killer T cells: naturally born for fighting

“…Activated NKT cells also induce DCs to up-regulate CCL17 acting with its receptor CCR4 expressed on CTLs, which is distinct from classical interaction of CCR5 and its three ligands, and might permit an additional level of selectivity in CTL attraction for NKT cell-licensed cross-priming [79,80] . A semipermeable transwell membrane co-culture system prevented the interaction between syngeneic spleen CD3 + T cells and NKT cells, which strongly suggests the synergy of NKT cells is direct cell-cell contact dependent [11] . In turn, murine hepatic NKT cells show negative regulatory activities on recruitment, activation and effector functions of intrahepatic γδT cells dependent on TLR3 signaling pathway [81] .…”

“…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 disorders [7,[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.…”