Psoriasis is a chronic inflammatory skin disease that is commonly associated with systemic inflammation. It affects approximately 1-3% of the global population, but the underlying mechanisms are not fully understood. Recent transcriptome analysis of T cells in psoriasis patients has revealed that the signaling lymphocyte activation molecule (SLAM) family receptor 2B4 (CD244) is significantly down-regulated, suggesting that it may play a role in psoriatic inflammation. However, no further studies have been conducted to confirm this hypothesis. To test this hypothesis, we applied Imiquimod (IMQ) topically to the skin of wild-type (WT) and 2B4-deficient (2B4-/-) mice to induce psoriatic skin inflammation. Our results showed that the clinical scores were significantly worse in 2B4-/- mice than in WT mice. Additionally, when we analyzed the immune cells in the skin of IMQ-treated WT or 2B4-/- mice, we found a significant decrease in the proportion of Vγ5 T cells in 2B4-/- mice compared to WT. Further analysis revealed that the IL-17 secretion from Vγ4 T cells was significantly increased in 2B4-/- mice. We also observed that Vγ5 T cells, which are known to play an important role in maintaining skin homeostasis, highly expressed 2B4. These findings present a previously unidentified role of 2B4 in Vγ5 T cells as a key receptor regulating the pathogenesis of psoriasis. Additional studies on the correlation between IL-17 production of Vγ4 by Vγ5 regulated by 2B4 are needed to gain new insights into the immunological mechanisms involved in psoriasis.