The brain is an immune-privileged site. To understand the mechanism of immune privilege in the brain, human cerebrospinal fluid (CSF) was examined for characteristics associated with fluids derived from other immune-privileged tissues. We first assayed for CSF suppression of effector T cell inflammatory activities. Primed T cells were activated with antigen and antigen-presenting cells in the presence of normal human or rabbit CSF, and T cell proliferation and interferon-γproduction were assayed. Human and rabbit CSF enhanced antigen-stimulated lymph node T cell proliferation and human CSF suppressed IFN-γproduction. T cell proliferation was suppressed by a low molecular weight (<5 kDA) fraction of CSF and by transiently acidified unfractionated CSF. Normal CSF, similar to fluids from other immune-privileged sites, has the capacity to suppress production of proinflammatory lym-phokines by antigen-stimulated effector T cells. Normal CSF also contains factors that have the potential to suppress effector T cell proliferation. Human CSF was assayed for factors known to mediate immunosuppression in other immune-privileged sites. Human CSF contained the immunosuppressive cytokine-transforming growth factor-β(1.7±0.6 ng/ml), and the immunosuppressive neuropeptides α-melanocyte stimulating hormone (60±11 pg/ ml), and vasoactive intestinal peptide (42±3 ng/ml). Much as fluids from other immune-privileged sites, CSF contains immunosuppressive cytokines that prevent activation of inflammatory-mediating (delayed-type hypersensitivity) T cells. This suggests that, similar to other immune-privileged sites, cytokines and neuropeptides mediate immunosuppression in the brain.