Stat6 signaling suppresses VLA-4 expression by CD8⁺ T cells and limits their ability to infiltrate tumor lesions in vivo

VLA-4 plays a critical role in T cell trafficking into inflammatory sites. Our recent studies have suggested that VLA-4 expression on CD8⁺ T cells is negatively controlled by IL-4 and serves as a functionally distinguishing variable for why Type-1, but not Type-2, CD8⁺ T cells are able to traffic into tumors. In this study, using in vitro culture of murine CD8⁺ T cells under Type-1 and Type-2 cytokine conditions, we show that IL-4-mediated down-regulation of VLA-4 expression is completely abrogated in Stat6-deficient CD8⁺ T cells. Conversely, CD8⁺ T cells expressing a constitutively active mutant form Stat6 (Stat6VT) failed to express VLA-4 even in the absence of IL-4-stimuIation. Notably, Type-2 CD8⁺ T cells developed from Stat6^-/- but not wild-type mice were competent to migrate into tumor lesions in vivo. These results suggest that Stat6-signaling is necessary and sufficient to restrict CD8⁺ T cell expression of VLA-4 (by IL-4), thereby serving as a regulator for CD8 ⁺ T cell infiltration into tumors.