| Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that is believed to be caused by erroneous activation of T cells specific to CNS antigens. There is considerable variation in the disease course and clinical signs due to different patterns of inflammation within the CNS in MS patients. To understand the basis for differential lesion distribution in the CNS of MS patients, we developed a novel model using myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in major histocompatibility complex (MHC) congenic mice. C3HeB/Fej (H-2 k) mice develop an atypical and severe form of EAE with extensive inflammation in the brain, spinal cord and optic nerve. In contrast, C3H.SW mice, which are congenic for H-2b, develop a chronic, ascending paralysis with inflammation restricted to the spinal cord and optic nerve. CD8+ T cells and B cells are dispensable for the atypical disease and brain inflammation in C3HeB/Fej mice, while CD4+ T cells are required.; Additional studies identify a novel mechanism that governs the differential ability to initiate inflammation in the brain. In genetically identical mice, MOG35-55/H-2b- and MOG79-90/H-2k-specific CD4 + T cells preferentially initiate inflammation in the spinal cord, while MOG97-114/H-2k-specific CD4+ T cells preferentially initiate inflammation in the brain, and not the spinal cord. The MOG97-114- specific T cell population has a significantly higher TH17:T H1 ratio and functional avidity compared to MOG35-55- and MOG79-90- specific T cells. Importantly, we demonstrate that the TH17:T H1 ratio, and not the absolute number, of T cells producing either interleukin 17 (TH17) or interferon-gamma (TH1) determines whether inflammation occurs in the brain or spinal cord. Thus, the effector T cell requirements for inducing inflammation in the brain or the spinal cord are different emphasizing the importance of the target organ in the tissue-specific regulation of inflammation. In summary, the pathogenicity of a T cell population is defined by the relative frequency of TH17 and TH1 cells rather than a single subset. These data elucidate a critical mechanism governing lesion distribution in the CNS, and have significant implications for MS therapies targeting T cell effector function. |
