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Lineage-specific control of superantigen-induced cell death by the protein tyrosine kinase p56(lck)
J M Penninger1, V A Wallace, T Molina
1Amgen Institute, Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, Canada.
Abstract:
Cell fate decisions in developing T cells depend on signal transduction via the Ag-specific TCR. Although the same TCR can signal for survival or cell death, specific signals that lead to cellular activation or death have not been identified. To study the role of the src tyrosine kinase p56(lck) in cell death of developing T cells, we introduced endogenous mouse mammary tumor retroviruses encoding superantigens (SAG) into p56(lck)-deficient mice. We show that clonal deletion of SAG-reactive CD4+ T cells does occur in p56(lck) -/- mice. Clonal deletion was also evident in CD4+ cells expressing TCRVbeta7, which has low affinity for Mls-1a. However, clonal deletion did not occur in SAG-reactive CD8+ T cells from p56(lck) -/- mice. Deletion of cells expressing SAG-reactive TCRVbeta chains was apparent in CD4+ single-positive but not in CD8+ single-positive thymocytes. Both CD4+ and CD8+ peripheral T cells from Mls-1b p56(lck) -/- mice responded to Mls-1a in vitro. However, CD8+ T cells from Mls-1a p56(lck) -/- mice that did not undergo deletion could not respond to Mls-1a, indicating that these cells are functionally unresponsive. These data show that p56(lck) is not required for clonal deletion of SAG-reactive CD4+ lymphocytes, including CD4+ cell expressing TCRs with low affinity for the SAG. However, p56(lck) appears to be an important signal transduction molecule involved in deletion of SAG-reactive CD8+ T cells.
Insights
The src tyrosine kinase p56(lck) is not essential for clonal deletion of CD4+ T cells but plays a key role in the elimination of CD8+ T cells during T cell development.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- T cell development involves critical cell fate decisions regulated by T cell receptor (TCR) signaling.
- Specific TCR signals determining T cell survival versus death remain largely unidentified.
- The role of the src tyrosine kinase p56(lck) in T cell apoptosis is under investigation.
Purpose of the Study:
- To investigate the function of p56(lck) in the clonal deletion of developing T cells.
- To determine if p56(lck) is required for the elimination of T cells that recognize superantigens (SAG).
Main Methods:
- Utilized p56(lck)-deficient mice and endogenous mouse mammary tumor retroviruses encoding SAG.
- Analyzed clonal deletion of CD4+ and CD8+ T cells in response to SAG.
- Assessed in vitro T cell responses to SAG in p56(lck) -/- mice.
Main Results:
- Clonal deletion of SAG-reactive CD4+ T cells occurred in p56(lck) -/- mice, even for T cells with low-affinity TCRs.
- Clonal deletion of SAG-reactive CD8+ T cells was impaired in p56(lck) -/- mice.
- Peripheral CD8+ T cells from p56(lck) -/- mice that escaped deletion were functionally unresponsive.
Conclusions:
- p56(lck) is dispensable for the clonal deletion of CD4+ T cells, including those with low-affinity TCRs.
- p56(lck) is crucial for the signal transduction required for the deletion of CD8+ T cells recognizing SAG.