The invention provides compositions and methods for regulating immune responses. In one embodiment, compositions of the invention include one or more SALM5-HVEM antagonists that are able to induce inflammation in the CNS or an immune privileged tissue. In another embodiment, compositions of the invention include one or more SALM5-HVEM agonists that are able to inhibit inflammation in the CNS or an immune privileged tissue. Therapeutic uses for SALM5-HVEM antagonists and agonist are also included in the invention.