A new role for CD28 in the survival of autoreactive T cells in the periphery after chronic exposure to autoantigen

Recent work demonstrates that costimulatory molecules play a critical role for clonal deletion of autoreactive T cells in the thymus. The role of CD28 in the survival of autoreactive T cells in the periphery, however, has not been reported. Here we demonstrate that while mutation of the CD28 gene consistently increased the burden of autoreactive T cells in the thymus, such an increase was not always found in the periphery, as the CD28(-/-) autoreactive T cells disappeared in the spleen over a period between 4 and 10 weeks. The disappearance of autoreactive T cells associates with a diminished induction of Bcl-2 protein by the self antigen and an increased proportion of apoptotic cells in the periphery. Moreover, the elimination of autoreactive T cells in the periphery requires chronic stimulation by the self antigen, as adoptive transfer analysis revealed no enhancement of apoptosis in CD28(-/-) T cells in antigen-bearing hosts over a 3 day period. Thus, CD28 plays a significant role in both clonal deletion and survival of autoreactive T cells after chronic exposure to autoantigens, resulting in opposite effects on the burden of autoreactive T cells.