Detuning CD8 T cells: down-regulation of CD8 expression, tetramer binding, and response during CTL activation
Zhengguo Xiao1, Matthew F Mescher, Stephen C Jameson
1Center for Immunology and 2Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455.
Insights
CD8 T cell expression temporarily decreases during infection, reducing antigen sensitivity. This "detuning" focuses immune responses on infected cells and protects bystander cells.
Area of Science:
- Immunology
- Cellular Biology
- Infectious Disease
Background:
- CD8 is essential for T cell recognition of peptide/MHC class I ligands.
- CD8 T cell activation typically involves down-regulation of CD8 expression.
Purpose of the Study:
- To investigate the regulation and functional consequences of transient CD8 down-regulation during T cell activation in vivo.
- To understand the role of type I interferon (IFN-I) and antigen in CD8 down-regulation.
Main Methods:
- In vivo studies using vaccinia virus and Listeria monocytogenes (LM) infection models.
- Analysis of CD8 T cell surface expression and mRNA levels.
- Assessment of T cell sensitivity using class I/peptide tetramers.
- Experiments with IFN-I receptor-deficient T cells.
Main Results:
- Loss of CD8 expression during LM and vaccinia virus responses correlated with reduced T cell sensitivity to antigen.
- CD8 down-regulation occurred despite sustained mRNA expression, indicating post-transcriptional regulation.
- CD8 levels recovered during memory cell differentiation.
- CD8 loss was dependent on both IFN-I signaling and antigen recognition.
Conclusions:
- Transient CD8 down-regulation, or CTL "detuning," is a regulated process during effector T cell differentiation.
- This mechanism may enhance the focus of effector responses on high-antigen target cells (e.g., infected cells).
- CD8 detuning could limit collateral damage to bystander cells during immune responses.
Abstract:
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. 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. 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 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. IFN-I alone was not sufficient to drive CD8 down-regulation, however, as antigen was also required for CD8 loss. 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.
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