PLZF-expressing CD4(+) T cells promote tissue-resident memory T cells in breaking immune tolerance in allergic asthma via IL-15/IL-15Rα signaling.

BACKGROUND: Allergic asthma is a chronic airway disease characterized by an allergic response and altered immune tolerance. CD4(+) tissue-resident memory T (TRM) cells are crucial in the chronic and relapsing pathogenesis of asthma. Furthermore, promyelocytic leukemia zinc finger (PLZF) is an essential transcription factor involved in asthmatic tolerance and has been implicated in the regulation of CD4(+)CD44(+) memory T cells. However, the role of CD4(+) TRM cells in asthmatic tolerance, as well as their potential modulation by PLZF, remain unclear. Therefore, in the current study, we explore the role of CD4(+) TRM cells in asthmatic immune tolerance and as well as the regulatory role of PLZF in this process. METHODS: To elucidate the role of CD4(+) TRM cells in immune tolerance, asthma memory mouse models were treated with the immunomodulator FTY720. Subsequently, CD4(+) T cells were isolated from the lungs and spleens and transferred to oral tolerance mouse models. To explore the regulation of PLZF in CD4(+) TRM cells, asthma and oral tolerance were established in Zbtb16(flox/flox) CD4(Cre) and wild-type mice. Flow cytometry, histological analysis, and cytokine measurements were performed to characterize the immune response. The regulatory activity of PLZF on CD4(+) TRM cells was analyzed through quantitative proteomics and verified in vitro and vivo. RESULTS: The CD4(+) TRM cell proportion positively correlated with the pathological phenotypes and molecular characteristics of asthma. Adoptive transfer of CD4(+) TRM cells induced asthmatic phenotypes. This suggested that CD4(+) TRM cells contributed to the pathogenesis of asthma. Conditional knockout of PLZF substantially reduced the proportion of CD4(+) TRM cells, relieved asthmatic symptoms, and suppressed the interleukin (IL)-15/IL-15Rα signaling pathway. Furthermore, exposure to the IL-15Rα agonist restored asthma-related Th2 inflammation, accompanied by a markedly increased proportion of CD4(+) TRM cells. Meanwhile, IL-15 and ovalbumin(OVA)-primed Beas2b supernatant co-stimulation in vitro enhanced the differentiation of pulmonary PLZF-expressing CD4(+ )T cells into CD4(+) TRM cells.  CONCLUSIONS: This study identified CD4(+) TRM cells as key mediators of immune tolerance in asthma. This process is regulated by the transcription factor PLZF in CD4(+) T cells through IL-15/IL-15Rα signaling. Thus, targeting PLZF or the IL-15/IL-15Rα pathway may represent a promising therapeutic strategy for treating asthma.