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Altered development of CD8+ T cell lineages in mice deficient for the Tec kinases Itk and Rlk
Christine Broussard1, Christine Fleischacker, Christine Fleischecker
1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
Mutations affecting the Tec kinases Itk and Rlk decrease T cell receptor-induced Ca(2+) mobilization and Erk kinase activation and impair both positive and negative thymic selection. Itk(-/-) and Rlk(-/-)Itk(-/-) mice also have decreased CD4:8 T cell ratios, suggestive of altered CD4:8 lineage commitment. Nonetheless, we find that CD8 single-positive (SP) thymocytes and peripheral CD8(+) T cells in these mice do not resemble conventional CD8(+) T cells. Instead, these cells express memory markers, rapidly produce interferon-gamma, and can be selected on hematopoietically derived cells, similar to MHC class Ib-restricted "innate-type" lymphocytes. Itk deficiency also greatly increases the number of cells selected by MHC class Ib. Expression of a hypersensitive Erk2 mutant partially corrects the CD8(+) T cell phenotypes in Itk(-/-) mice, arguing that altered signaling permits development of this innate-type CD8(+) cell population. Our results suggest that Tec kinases differentially regulate development of conventional versus nonconventional lymphocytes.
Insights
Mutations in Tec kinases Itk and Rlk disrupt T cell development, leading to an increase in innate-type CD8+ T cells. This suggests Tec kinases regulate distinct lymphocyte populations.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Tec kinases, including Itk and Rlk, are crucial for T cell receptor (TCR) signaling.
- Impaired TCR signaling affects T cell development and selection in the thymus.
- Altered CD4:CD8 T cell ratios suggest issues with T cell lineage commitment.
Purpose of the Study:
- To investigate the role of Tec kinases Itk and Rlk in T cell development and selection.
- To characterize the phenotype of CD8+ T cells in Itk and Rlk deficient mice.
- To understand the signaling pathways regulating conventional versus nonconventional T cell development.
Main Methods:
- Analysis of T cell populations in Itk(-/-) and Rlk(-/-)Itk(-/-) mice.
- Flow cytometry to assess T cell markers and activation.
- Assessment of cytokine production, including interferon-gamma.
- Genetic manipulation using a hypersensitive Erk2 mutant.
Main Results:
- Mutations in Itk and Rlk impair TCR-induced Ca(2+) mobilization and Erk activation.
- These mutations lead to defects in thymic selection and altered CD4:CD8 T cell ratios.
- CD8+ T cells in mutant mice exhibit characteristics of innate-type lymphocytes, including memory markers and rapid IFN-gamma production.
- Itk deficiency increases the selection of T cells by MHC class Ib.
- Expression of a hypersensitive Erk2 mutant partially rescues CD8+ T cell phenotypes.
Conclusions:
- Tec kinases Itk and Rlk play differential roles in the development of conventional and nonconventional T cells.
- Altered signaling pathways mediated by Tec kinases permit the development of innate-type CD8+ T cells.
- These findings shed light on the regulation of distinct lymphocyte lineages and their selection processes.
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