Surface expression of α4 integrin by CD4 T cells is required for their entry into brain parenchyma

Abstract

Cloned CD4 T cell lines that recognize the Ac1-16 peptide of myelin basic protein bound to I-Au were isolated and used to analyze the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). T helper type 1 (Th1) clones induced disease, while Th2 clones did not. Using variants of a single cloned Th1 line, the surface expression of α4 integrins (very late antigen 4 [VLA-4]) was identified as a major pathogenic factor. Encephalitogenic clones and nonencephalitogenic variants differ by 10-fold in their level of surface expression of α4 integrin and in their ability to bind to endothelial cells and recombinant vascular cell adhesion molecule 1 (VCAM-1). The α4 integrin-high, disease-inducing cloned Th1 T cells enter brain parenchyma in abundance, while α4 integrin-low, nonencephalitogenic Th1 cells do not. Moreover, antibodies to α4 integrin, its ligand VCAM-1, and intercellular adhesion molecule 1 all influence the pathogenicity of this encephalitogenic clone in vivo. The importance of the expression of VLA-4 for encephalitogenicity is not unique to cloned T cell lines, as similar results were obtained using myelin basic protein-primed lymph node T cells. α4 integrin levels did not affect antigen responsiveness or production of the Th1 cytokines interleukin 2, interferon 7, and lymphotoxin/tumor necrosis factor β; and antibodies against α4 integrin did not block antigen recognition in vitro. Thus, we conclude that surface expression of α4 integrin is important in CD4 T cell entry into brain parenchyma. A general conclusion of these studies is that α4 integrins may be crucial in allowing activated effector T cells to leave blood and enter the brain and other tissues to clear infections.