REGULATION OF BRAIN-DERIVED T-CELLS DURING ACUTE CENTRAL-NERVOUS-SYSTEM INFLAMMATION

The unique immunologic environment of the central nervous system (CNS) regulates most local inflammatory responses. In some circumstances, h owever, immune-mediated injury to the brain can occur, To understand h ow lymphocytes are regulated within the CNS during an inflammatory res ponse that does not produce immunopathology, we have studied T cells i solated from the brains of mice with Sindbis virus (SV) encephalitis. Even though they express activation markers, these T cells are arreste d in the cell cycle and do not proliferate in vitro. Altered phosphory lation of the retinoblastoma gene product, a critical cell cycle regul ator, appears to mediate this effect. Furthermore, while brain-derived T cells generate IFN-gamma, IL-4, and IL-10, these T cells are defici ent in IL-2 production compared with peripheral T cells. This pattern of cytokine production occurs in cells that do not activate NF-kappa B normally. When T cells producing both IL-2 and IFN-gamma are adoptive ly transferred into SV-infected mice, some of these cells traffic into the brain. Those that enter the brain selectively down-regulate IL-2 production over time. Since normal brain lipids can inhibit IL-2 produ ction and T cell proliferation in vitro, these substances may mediate these same effects in vivo. Collectively, these data show that the loc al environment of the CNS during SV encephalitis exerts a complex regu latory effect on T cells that are recruited into the brain. We specula te that this effect serves to prevent excessive local T cell reactivit y. Whether and how this regulation might fail in the setting of autoim mune neurologic disease remains to be explored.