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

Abstract

CD8low ͉ co-receptor tuning ͉ T cell activation ͉ cytotoxic T lymphocytes ͉ cytokines T he CD8␣␤ co-receptor amplifies the CD8 ϩ T cell response to peptide/MHC Class I complexes on antigen-presenting cells (APC) by at least four mechanisms. First, CD8 binding to nonpolymorphic regions of the MHC molecule and ␤2-microglobulin is thought to stabilize the interaction between the TCR and peptide/MHC complexes (1); second, CD8 binding to the MHC augments TCR signaling via activation of p56 lck and LAT (2, 3); third, CD8 is thought to induce the co-localization of receptor complex molecules onto lipid rafts (4); and fourth, CD8 induces a conformational change in CD3 that is necessary for signal transduction (5). The effect can be dramatic: for example, transfection of CD8-negative T cells bearing lowaffinity TCR with CD8␣ or CD8␣/CD8␤ has been reported to amplify peptide sensitivity by factors of 10 7 to 10 9 (6). Modulation of surface CD8 expression on naive and effector cells can therefore alter the threshold peptide/MHC levels required to trigger proliferation, cytokine production and target cell lysis (7, 8), effectively ''tuning'' the T cell response.Surface CD8 levels can be controlled by distinct antigen-and cytokine-dependent mechanisms. The former has been observed as a transient response to TCR activation (9) and in peripheral tolerance where chronic antigen exposure can be associated with stable CD8 down-regulation at the T cell surface (7, 10, 11). Cytokine-dependent CD8 down-regulation was first reported by Erard et al. (12) who demonstrated that exposure of naïve CD8 ϩ T cells to IL-4 during activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin in vitro led to loss of surface CD8 and CD8␣ RNA, induction of a type 2 cytokine profile and the absence of cytolytic activity. We extended these studies to show that the presence of IL-4 in the first few days of primary activation with antibodies to the TCR, CD8 and CD11a (antireceptor Ab) or alloantigens promoted the development of poorly cytolytic, type 2 effector cells that retained their TCR but displayed reduced or undetectable surface CD8 expression; essentially all conventional CD8 ϩ T cells could eventually give rise to committed CD8 low cells that maintained this phenotype in the absence of continued IL-4 exposure (13,14). By contrast, Park et al. have recently reported that IL-4 and other ␥c cytokines up-regulated surface CD8 levels when CD8 ϩ T cells were cultured in vitro without a TCR stimulus (7).IL-4 and IFN-␥ reciprocally regulate a number of lymphocyte functions, including the expression of type 1 and type 2 cytokines by CD4 ϩ and CD8 ϩ effector cells (15,16). The present study was therefore undertaken to determine whether this was also true for CD8 expression in newly activated CD8 ϩ T cells. We show here that IFN-␥ not only counteracts the down-regulatory effect of IL-4 on CD8 mRNA and protein levels but also contributes to the maintenance of CD8 levels in the absence of exogenous IL-4. The reciprocal effects of IL-4 and IFN-␥ we...

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