REGULATION OF CD28 COSTIMULATION IN HUMAN CD8(-CELLS() T)

Optimal stimulation and prevention of anergy in T cells requires signa ling through the CD28 molecule. During HIV disease progression, CD28 e xpression is lost, particularly on CD8(+) T cells. Because alterations in cytokine production patterns occur during HIV infection, we determ ined whether CD8(+) T cell phenotype or function was affected by cytok ine environment. Treatment of CD8(+) T cells with IL-4 decreased level s of both CD28 surface expression and message and increased CD8 expres sion. Furthermore, CD8(+) T cells that had down-regulated CD28 had red uced proliferative capacity. The inhibitory effects of CD28 reduction could be compensated either by increased anti-CD3 or by exogenous IL-2 , suggesting that the strength of T cell signaling necessary for the p roduction of IL-2 and subsequent proliferation is negatively regulated by IL-4, CD8(+) subpopulations with differential CD28 expression prod uced different patterns of cytokines, particularly IL-2 and IFN-gamma. Furthermore, CD8(+) T cells that had reduced CD28 levels but made the ir own IL-2 were able to proliferate in response to TCR stimulation. T hese results suggest that loss of CD28 expression and CD8 T cell funct ion can be regulated by the cytokine environment, which may be altered during HIV disease progression. Whether the dysfunction of CD8(+) T c ells in HIV infection occurs by such a mechanism is the subject of fut ure investigation.