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Stat6 Signaling Suppresses VLA-4 Expression by CD8⁺ T Cells and Limits Their Ability to Infiltrate Tumor Lesions In Vivo¹

Kotaro Sasaki^*, Xi Zhao^*,, Angela D. Pardee, Ryo Ueda, Mitsugu Fujita, Sarita Sehra, Mark H. Kaplan, Lawrence P. Kane, Hideho Okada and Walter J. Storkus^2,*,

^* Department of Dermatology, Department of Immunology, and Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Pediatrics, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants P01 CA100327 and R01 CA63350 (to W.J.S.), and R01 NS055140 (to H.O.).

² Address correspondence and reprint requests to Dr. Walter J. Storkus, Department of Dermatology, University of Pittsburgh Medical Center, W1041.2 Biomedical Sciences Tower, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: storkuswj{at}upmc.edu

³ Abbreviations used in this paper: IRS, insulin receptor substrate; WT, wild type; TIL, tumor-infiltrating lymphocyte.