THE OX-40 RECEPTOR PROVIDES A POTENT COSTIMULATORY SIGNAL CAPABLE OF INDUCING ENCEPHALITOGENICITY IN MYELIN-SPECIFIC CD4(-CELLS() T)

The OX-40 receptor, a member of the nerve growth factor/tumor necrosis factor receptor gene family, is expressed preferentially on autoreact ive CD4(+) T cells isolated from the site of inflammation in rats with clinical signs of experimental autoimmune encephalomyelitis (EAE). To examine whether the OX-40 receptor has biologic relevance to T cell f unction, we evaluated the ability of a rat OX-40 receptor-specific ant ibody to co-stimulate a myelin basic protein (MBP)reactive CD4(+) T ce ll line. The anti-OX-40 antibody provided a potent co-stimulatory sign al to CD4(+) T cells when added in conjunction with a submitogenic dos e of anti-CD3, but the anti-OX-40 antibody alone did not produce a mit ogenic response. The magnitude and dose-response of anti-OX-40 co-stim ulation was virtually identical to the signal delivered to T cells whe n cultured with anti-CD28 in conjunction with anti-CD3. MBP-specific T cells stimulated with both anti-CD3 and anti-OX-40 antibodies express ed increased mRNA and protein for IL-2 when compared to anti-CD3 alone . MBP-specific T cells stimulated with both anti-CD3 and anti-OX-40 an tibodies were also able to induce EAE when transferred into naive Lewi s rats. In contrast, cells stimulated with anti-CD3 alone were not enc ephalitogenic. These data suggest that the function of the OX-40 recep tor on activated T cells is to provide an alternative pathway for T ce ll co-stimulation that may be similar in potency to the CD28-mediated signal.