Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma.

Abstract

Summary Cloned CD4 T cell lines that recognize the Ac1-16 peptide of myelin basic protein bound to I-A" were isolated and used to analyze the immunopathogeuesis of experimental autoimmune encephalomyelitis (EAE). T helper type 1 (Thl) clones induced disease, while Th2 clones did not. Using variants of a single cloned Thl line, the surface expression of o~4 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 a4 integrin and in their ability to bind to endothelial cells and recombinant vascular cell adhesion molecule 1 (VCAM-1). The cx4 integrin-high, disease-indudng cloned Thl T cells enter brain parenchyma in abundance, while ~x4 integrin-low, nonencephalitogeuic Thl cells do not. Moreover, antibodies to o~4 integrin, its ligand VCAM-1, and intercellular adhesion molecule 1 all influence the pathogenicity of this eucephalitogenic 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, o~4 integrin levels did not affect antigen responsiveness or production of the Thl cytokines interleukin 2, interferon 7, and lymphotoxin/tumor necrosis factor fl; and antibodies against o~4 integrin did not block antigen recognition in vitro. Thus, we conclude that surface expression of oe4 integrin is important in CD4 T cell entry into brain parenchyma. A general conclusion of these studies is that or4 integrins may be crucial in allowing activated effector T cells to leave blood and enter the brain and other tissues to clear infections.

Cytokine expression by inflammatory cells obtained from the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis induced by inoculation with myelin basic protein and adjuvants

“…Our findings of IL-2 mRNA expression throughout the clinical disease are consistent with previous studies indicating the importance of IL-2 in EAE. IL-2 is known to be present in the CNS in EAE (Baker et al, 1991;Merrill et al, 1992;Renno et al, 1994) and encephalitogenic T cell clones secrete IL-2 (Ando et al, 1989;Baron et al, 1993). Expression of IFN-(relative to -actin) was observed throughout the course of the disease, with a peak on days 17-19, during late clinical recovery.…”

“…EAE is characterized by infiltration of the nervous system with activated T lymphocytes and macrophages (Raine, 1984;McCombe et al, 1992). Cloned encephalitogenic T cells secrete interleukin-2 (IL-2) and interferon-(IFN-) (Ando et al, 1989;Baron et al, 1993). Thus, encephalitogenic cells are Th1-like cells, as defined by the original concept of Mosmann and Coffman (1989) that CD4 + T cells produce either IL-2 and IFN-(Th1 cells) or IL-4, IL-5 and IL-10 (Th2 cells).…”

Intracerebral injection of myelin basic protein (MBP) induces inflammation in brain and causes paraplegia in MBP-sensitized B6 mice

“…The transient decrease in MBP-reactive or VLA-4 þ cells at 24 h (1 day before clinical symptoms) followed by an increase thereafter is compatible with the hypothesis that activated T cells were recruited into the brain from the cervical lymph node. Baron et al [20] demonstrated that surface expression of VLA-4 was important for CD4 þ T cell entry into brain parenchyma. The VLA-4 integrins may be crucial in allowing activated effector T cells to leave the blood and enter the brain.…”

E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice

“…After the seminal study by Yednock et al (2) demonstrating that Abs blocking ␣ 4 integrin inhibit EAE by blocking T cell interaction with the BBB, numerous following studies confirmed and extended the predominant involvement of ␣ 4 integrin/VCAM-1 in inflammatory cell recruitment into the CNS in different EAE models in a number of species (3)(4)(5)(6). Using intravital microscopy, we have demonstrated that the recruitment of encephalitogenic T cell blasts across the spinal cord white matter microvasculature in healthy mice depends on ␣ 4 integrin-mediated initial capture and G protein-dependent arrest (7).…”

“…I n multiple sclerosis (MS), 3 and in its animal model, experimental autoimmune encephalomyelitis (EAE), circulating immune cells gain access to the CNS and cause inflammation, blood-brain barrier (BBB) breakdown, and demyelination, which all set the stage for the development of the clinical manifestations of this disabling disease. EAE is a T cell-mediated autoimmune disease, which can be induced either by immunization with myelin Ags or by the transfer of encephalitogenic T cells in susceptible rodent strains including mice.…”