To investigate the role of the costimulatory molecule CD226 in asthma pathogenesis, we produced a CD4⁺ T-cell-specific CD226 knockout mice model (Cd226^ΔCD4) and induced airway allergic inflammation by administering ovalbumin (OVA). Our results revealed alleviated lung inflammation, decreased levels of OVA-specific IgE, and increased levels of IL-10 in the serum of Cd226^ΔCD4 mice (P < 0.05). Moreover, IL-10 levels in CD4⁺ T cells were significantly elevated in the mediastinal lymph node, spleen, and Peyer's patches in the Cd226^ΔCD4 mice compared with those in controls (P < 0.05 to P < 0.01). Notably, there was a significantly higher IL-10 mRNA levels in the large intestine of the mice (P < 0.05). The protective effect of CD226 deficiency is also associated with the accumulation of gut TCRγδ⁺ intraepithelial lymphocytes and reversion of the gut microbiome dysbiosis. The Bacteroidetes-to-Firmicutes ratio and the abundance of Akkermansia increased in the absence of CD226 after OVA treatment. Our data reveal the synchronous changes in the lung and intestine in OVA-treated CD226-knockout mice, supporting the gut-lung axis concept and providing evidence for novel therapeutic approaches for asthma.