IL-4 suppresses very late antigen-4 expression which is required for therapeutic Th1 T-cell trafficking into tumors.
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.
Sasaki
Kotaro
K
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Pardee
Angela D
AD
Qu
Yanyan
Y
Zhao
Xi
X
Ueda
Ryo
R
Kohanbash
Gary
G
Bailey
Lisa M
LM
Okada
Hideho
H
Muthuswamy
Ravikumar
R
Kalinski
Pawel
P
Basse
Per H
PH
Falo
Louis D
LD
Storkus
Walter J
WJ
D000818:Animals; D019138:Antibodies, Blocking; D016827:CD8 Antigens / Q000096:biosynthesis; D002465:Cell Movement; D016219:Immunotherapy, Adoptive; D039041:Integrin alpha4beta1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D039121:Integrin alpha6beta1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D019138:Antibodies, Blocking; D016827:CD8 Antigens; D039041:Integrin alpha4beta1; D039121:Integrin alpha6beta1; D015847:Interleukin-4