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

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.