![]() CD8 low subpopulations have been reported during chronic diseases ( 16– 18), but CD8 down-regulation also occurs during acute immune responses to pathogens ( 19– 21) and cell lines ( 22). Furthermore, down-regulation of CD8 has been suggested as one of the mechanisms for peripheral tolerance ( 12– 15). However, CD8 expression can be inhibited by certain cytokines, including IL-2, -4, and -15, on activated T cells ( 7– 11). ![]() CD8 expression has been thought to be stable during a CD8 T cell response, and it is commonly used as the marker to define cytotoxic T cells. CD8 engagement can enhance peptide sensitivity by 1 million–fold or more ( 2), and it is required for a stable complex between class I and the TCR ( 5, 6). These results suggest that CD8 effector T cell differentiation involves a transient down-regulation of antigen sensitivity (CTL “detuning”), via reduced CD8 expression, a feature that may focus the effector response on target cells expressing high levels of antigen (e.g., infected cells), while limiting collateral damage to bystander cells.ĬD8 is an important coreceptor for TCR during CD8 T cell activation by peptide/class I MHC ligands ( 1– 4). IFN-I alone was not sufficient to drive CD8 down-regulation, however, as antigen was also required for CD8 loss. We determined that during response to LM, CD8 down-regulation is regulated by T cell reactivity to type I interferon (IFN-I) because CD8 loss was averted on IFN-I receptor–deficient T cells. Loss of CD8 cell surface expression occurs despite sustained mRNA expression, and CD8 levels return to normal levels during differentiation of memory cells, indicating a transient effect. We report that loss of CD8 expression early during in vivo responses to vaccinia virus or Listeria monocytogenes (LM) correlates with decreased T cell staining with specific class I/peptide tetramers and reduced CD8 T cell sensitivity for antigen. CD8 is critical for T cell recognition of peptide/class I major histocompatability complex ligands, yet is down-regulated during activation of CD8 T cells.
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