Selective Expansion of Double-Negative iNKT Cells Inhibits the Development of Atopic Dermatitis in Vα14 TCR Transgenic NC/Nga Mice by Increasing Memory-Type CD8⁺ T and Regulatory CD4⁺ T Cells

Spontaneous development of atopic dermatitis (AD) in NC/Nga (NC) mice has been attributed to a deficiency in invariant NK T (iNKT) cells. To elucidate the precise role of iNKT cells in AD development of NC mice, we employed two distinct murine models of iNKT cell over-representation: Vβ8 TCR congenic and Vα14 TCR transgenic NC mice. We found that Vα14 TCR transgenic (Vα14^Tg) but not Vβ8 TCR congenic (Vβ8^Cg) NC mice exhibited reduced AD development, which was attributed to both quantitative and qualitative changes in iNKT cells such as a biased expansion of the double-negative iNKT subset. Adoptive transfer experiments confirmed that iNKT cells from Vα14^Tg mice but not from Vβ8^Cg mice were responsible for protecting NC mice from AD development. Double-negative iNKT cells from Vα14^Tg NC mice showed a T helper type-1‒dominant cytokine profile, which may account for the expansion of CD4⁺ regulatory T cells and memory-type CD8⁺ T cells. Furthermore, the adoptive transfer of CD8⁺ T cells from Vα14^Tg NC mice into AD-susceptible wild-type NC mice suppressed AD in recipient NC mice. Taken together, our results have identified double-negative iNKT cells as promising cellular targets to prevent AD pathogenesis.