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-stimulation. 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.
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kotaro
K
Sasaki
Xi
X
Zhao
Angela D
AD
Pardee
Ryo
R
Ueda
Mitsugu
M
Fujita
Sarita
S
Sehra
Mark H
MH
Kaplan
Lawrence P
LP
Kane
Hideho
H
Okada
Walter J
WJ
Storkus
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D050800:STAT6 Transcription Factor; D019010:Vascular Cell Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases