IL-4 suppresses very late antigen-4 expression which is required for therapeutic th1 t-cell trafficking into tumors

Kotaro Sasaki, Angela D. Pardee, Yanyan Qu, Xi Zhao, Ryo Ueda, Gary Kohanbash, Lisa M. Bailey, Hideho Okada, Ravikumar Muthuswamy, Pawel Kalinski, Per H. Basse, Louis D. Falo, Walter J. Storkus

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Murine CD4 T cells cultured under type 1 polarizing conditions selectively express significantly higher levels of the very late antigen (VLA)-4 and VLA-6 integrins when compared with T cells cultured under type 2 or nonpolarizing (type 0) conditions. This difference appears due to the action of interleukin (IL)-4, as loss of VLA-4/-6 expression on Th cells was prevented by inclusion of neutralizing anti-IL-4 mAb during the initial culture period. We also observed that CD4 T cells deficient in Stat6, a critical component of the IL-4R signaling cascade, retained high levels of VLA-4 and VLA-6 expression, regardless of IL-4 status in the culture conditions. When applied to committed Th1 cells, rIL-4 readily inhibited VLA-4 and VLA-6 expression to levels observed for Th2 cells, without altering the type 1 functional status of these cells. Conversely, low levels of VLA-4/VLA-6 expressed by committed Th2 cells could not be resurrected by culture in the presence of the Th1-kines IL-12p70 and interferon-γ. Predictably, among the Th populations evaluated, Th1 cells alone adhered efficiently to, and were costimulated by, plate-bound VCAM-1 and laminin in a VLA-4-dependent or VLA-6-dependent manner, respectively. Finally, adoptive-transferred Th1 (but not Th2) cells developed from OT-II mice were uniquely competent to traffick into OVA M05 melanoma lesions in vivo, thereby enhancing the therapeutic benefits associated with cotransferred OVA-specific type 1 CD8 (OT-I) cells. These data suggest that treatment strategies capable of sustaining/enhancing VLA-4/VLA-6 expression on Th1 effector cells may yield improved clinical efficacy in the cancer setting.

Original languageEnglish
Pages (from-to)793-802
Number of pages10
JournalJournal of Immunotherapy
Volume32
Issue number8
DOIs
Publication statusPublished - 2009 Oct
Externally publishedYes

Keywords

  • IL-4
  • Melanoma
  • T helper-1
  • VLA-4
  • VLA-6

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology
  • Cancer Research

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