iNKT cells with high PLZF expression are recruited into the lung via CCL21‐CCR7 signaling to facilitate the development of asthma tolerance in mice

Abstract

Establishment of immune tolerance is crucial to protect humans against asthma. Promyelocytic leukemia zinc finger (PLZF) is an emerging suppressor of inflammatory responses. CCL21‐CCR7 signaling mediates tolerance development. However, whether PLZF and CCL21‐CCR7 are required for the development of asthma tolerance is unknown. Here, we found that Zbtb16 (coding PLZF) and Ccl21 were upregulated in OVA‐induced asthma tolerance (OT) lungs by RNA‐seq. PLZF physically interacted with GATA3 and its expression was higher in GATA3+ Th2 cells and ILC2s in OT lungs. Zbtb16‐knockdown in lymphocytes promoted the differentiation of CD3e+CD4+ T cells, particularly those producing IL‐4 and IL‐5. Moreover, iNKT cells with high expression of PLZF were recruited into the lungs via draining lymph nodes during tolerance. Blockade of CCL21‐CCR7 signaling in OT mice decreased the PLZF+ cell population, abolished CCR7‐induced PLZF+ iNKT recruitment to the lungs, enhanced Th2responses and exacerbated lung pathology. In OT mice, respiratory syncytial virus (RSV) infection impeded PLZF+ cell and CCR7+PLZF+ iNKT cellrecruitment to the lungs and increased airway resistance. Collectively, these results indicate that PLZF could interact with GATA3 and restrain differentiation of IL‐4‐ and IL‐5‐producing T cells, iNKT cells with high PLZF expression are recruited to the lungs via CCL21‐CCR7 signaling to facilitate the development of asthma tolerance.

Oral antibiotics relieve allergic asthma in post-weaning mice via reducing iNKT cells and function of ADRB2

“…As previously described ( 6 ), female Balb/c mice were divided into three groups (3-4 per group): (i) control group: OT was not induced in the first week, intraperitoneal injection (50 µl aluminum adjuvant in 75 µl phosphate-buffered saline [PBS]) was performed on day 15, and aerosol challenge (PBS) was performed on days 22–28; (ii) asthma group: OT was not induced in the first week, intraperitoneal sensitization (50 µg OVA and 50 µl aluminum adjuvant in 70 µl PBS) was performed on day 15, and aerosol challenge (10 mg/ml OVA in PBS) was performed on days 22–28; and (iii) OT group: OT was induced (using 10 mg/ml OVA dissolved in autoclaved drinking water) on days 1–7, intraperitoneal sensitization (50 µg OVA and 50 µl aluminum adjuvant in 70 µl PBS) was performed on day 15, and aerosol challenge (10 mg/ml OVA in PBS) was performed on days 22–28 ( Figure 1A ).…”

“…As previously described ( 6 ), results of RNA-sequence represented one experiment including 11 samples totally and n=3-4 in each groups. This project was based on the sequencing analysis platform of BGI Genomics Co Ltd. Bowtie2 was used to align clean reads to the genome sequence, and then used RSEM (a software package for RNA-seq reads to calculate gene and transcript subtype expression levels) to calculate the gene expression level of each sample.…”

“…However, the mechanisms underlying asthma and oral immune tolerance are complex. Using 4-week-old BALB/c mice provided with ovalbumin (OVA) - containing drinking water, we recently established an OVA - induced asthma tolerance (OT) mouse model ( 6 , 7 ). Here, we explored the effects of antibiotics on the development of asthma and established OT by providing mice with antibiotic drinking water, which is capable of altering their gut microenvironment.…”