IL-4 suppresses very late antigen-4 expression which is required for therapeutic Th1 T-cell trafficking into tumors.

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-gamma. 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.

• Authors: 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
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 32 Issue 8 Pg. 793-802 (Oct 2009) ISSN: 1537-4513 [Electronic] United States
• PMID: 19752754 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Blocking
• CD8 Antigens
• Integrin alpha4beta1
• Integrin alpha6beta1
• Interleukin-4

Topics

• Animals
• Antibodies, Blocking
• CD8 Antigens (biosynthesis)
• Cell Movement
• Immunotherapy, Adoptive
• Integrin alpha4beta1 (biosynthesis, genetics, immunology)
• Integrin alpha6beta1 (biosynthesis, genetics, immunology)
• Interleukin-4 (immunology, pharmacology)
• Melanoma, Experimental (immunology, pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Th1 Cells (drug effects, immunology, metabolism, pathology)
• Th2 Cells (drug effects, immunology, metabolism, pathology)