Interferon- gamma and interleukin-4 reciprocally regulate CD8 expression in CD8 super(+) T cells

The CD8 co-receptor can modulate CD8 super(+) T cell function through its contributions to T cell receptor (TCR) binding and signaling. Here we show that IFN- gamma and IL-4 exert opposing effects on the expression of CD8 alpha mRNA and surface CD8 protein during CD8 super(+) T cell activation. IL-4 caused down-regulation of surface CD8 on ovalbumin (OVA) sub(257-264)-specific TCR-transgenic OT-I CD8 super(+) T cells activated with OVA sub(257-264)-coated antigen presenting cells or polyclonal stimuli, and on wild type CD8 super(+) T cells activated with polyclonal stimuli. This effect was enhanced in each case when the cells lacked a functional IFN- gamma or IFN- gamma R gene. When WT or IFN- gamma -deficient OT-I CD8 super(+) T cells were analyzed 9 days after co-injection with control or IL-4-expressing OVA super(+) tumor cells into RAG-2 super(-/-) gamma c super(-/-) mice, CD8 levels were highest on WT donor cells from mice that received the control tumor and lowest on IFN- gamma -deficient donor cells from mice that received the IL-4-expressing tumor. The latter CD8 super(low) cells displayed markedly impaired binding of OVA sub(257-264)/MHC tetramers and peptide/MHC-dependent degranulation. The data reveal an unexpected role for IFN- gamma in tuning the CD8 co-receptor during primary CD8 super(+) T cell activation both in vitro and in vivo.