Immunosuppression by CD4(+) regulatory T cells induced by chronic retroviral infection

Normal levels of CD4(+) regulatory T cells are critical for the maintenance of immunological homeostasis and the prevention of autoimmune diseases. Ho wever, we now show that the expansion of CD4(+) regulatory T cells in respo nse to a chronic viral infection can lead to immunosuppression. Mice persis tently infected with Friend retrovirus develop approximately twice the norm al percentage of splenic CD4(+) regulatory T cells and lose their ability t o reject certain tumor transplants. The role of CD4(+) regulatory T cells w as demonstrated by the transmission of immunosuppression to uninfected mice by adoptive transfers of CD4(+) T cells. CD4(+) T cells from chronically i nfected mice were also immunosuppressive in vitro, inhibiting the generatio n of cytolytic T lymphocytes in mixed lymphocyte cultures. Inhibition occur red at the level of blast-cell formation through a mechanism or mechanisms involving transforming growth factor-beta and the cell surface molecule CTL A-4 (CD152). These results suggest a possible explanation for HIV- and huma n T cell leukemia virus-I-induced immunosuppression in the absence of T cel l depletion.