CD8(+) T regulatory cells (T regs) are elicited by unique antigen presenting cells during viral infections, by manipulation of co-stimulatory molecules, or in the development of tumors. CD8(+) T regs display antigen-specificity, which is most exquisitely manifested by the HLA-E-restricted cytolytic CD8(+) T regs in MS. There is evidence that some CD8(+) T regs also express organ specificity. In many cases, IFN-gamma is required for either the induction or expression of CD8(+) T regs. CD8(+) T regs can produce suppression directly by killing immune cells or indirectly by co-opting other cells to elaborate end-stage suppressive molecules such as TGF-beta, IL-10, and indoleamine dioxygenase (IDO).