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

The CD8 co-receptor can modulate CD8⁺ T cell function through its contributions to T cell receptor (TCR) binding and signaling. Here we show that IFN-γ and IL-4 exert opposing effects on the expression of CD8α mRNA and surface CD8 protein during CD8⁺ T cell activation. IL-4 caused down-regulation of surface CD8 on ovalbumin (OVA)_257–264-specific TCR-transgenic OT-I CD8⁺ T cells activated with OVA_257–264-coated antigen presenting cells or polyclonal stimuli, and on wild type CD8⁺ T cells activated with polyclonal stimuli. This effect was enhanced in each case when the cells lacked a functional IFN-γ or IFN-γR gene. When WT or IFN-γ-deficient OT-I CD8⁺ T cells were analyzed 9 days after co-injection with control or IL-4-expressing OVA⁺ tumor cells into RAG-2^−/−γc^−/− mice, CD8 levels were highest on WT donor cells from mice that received the control tumor and lowest on IFN-γ-deficient donor cells from mice that received the IL-4-expressing tumor. The latter CD8^low cells displayed markedly impaired binding of OVA_257–264/MHC tetramers and peptide/MHC-dependent degranulation. The data reveal an unexpected role for IFN-γ in tuning the CD8 co-receptor during primary CD8⁺ T cell activation both in vitro and in vivo.