Immune reactivity in the nervous system: modulation of T-lymphocyte activation by glial cells

Abstract

The vertebrate central nervous system (CNS) has been traditionally thought to be inaccessible for the passenger lymphocytes of the immune system. This does not seem to be the case: activated T-lymphocytes can readily cross the endothelial blood-brain barrier (BBB) and some glial cells, notably the astrocytes, seem to be programmed to act as most efficient and complex partners for antigen-specific T-lymphocytes. We used myelin basic protein (MBP) specific permanent rat T-lymphocyte lines as probes to assess the immune status of the CNS. These cells, upon activation in vitro, are able to transfer lethal, experimentally induced autoimmune-encephalomyelitis (EAE) to normal syngeneic recipients. Activated T-lymphocytes, but not resting ones, can break through the BBB irrespective of their antigen specificity. Immune surveillance of the CNS thus seems to be executed by activated T-lymphocytes. Having crossed the BBB, the activated T-cells interact with local glial cells by releasing factors, including interferon-gamma, which induced astrocytes to synthesize and express, on their membranes, class II major histocompatibility antigens (Ia determinants), which are critically required for immunogenic presentation of antigens to T-cells. Indeed, Ia-induced astrocytes of the CNS (and the Schwann cells of peripheral nerves) are efficient antigen presenter cells, which are able strongly to up-regulate antigen-reactive T-lymphocytes. In addition, it has recently been shown that at least some astrocytes are able to down-regulate immune cells. Some, but not all, astrocytes are capable of suppressing activation of T-cells. This suppression can be modulated by interferon-gamma, and is sensitive to irradiation. The question of whether suppression is mediated by direct cell-to-cell contact or via soluble mediators (e.g. apolipoprotein E) is under investigation. Astrocytes have been found to be most subtle regulators of immuno-competent T-cells. Most probably they are centrally involved in physiological immune reactivity of the CNS, and it will be tempting to learn how far glial cells are involved in transmitting regulatory signals between the immune and nervous systems.