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Impaired lymphocyte trafficking in mice deficient in the kinase activity of PKN1
Rana Mashud1, Akira Nomachi2, Akihide Hayakawa3
1Graduate School of Medicine, Kobe University, Kobe, 650-0017, Japan.
Abstract:
Knock-in mice lacking PKN1 kinase activity were generated by introducing a T778A point mutation in the catalytic domain. PKN1[T778A] mutant mice developed to adulthood without apparent external abnormalities, but exhibited lower T and B lymphocyte counts in the peripheral blood than those of wild-type (WT) mice. T and B cell development proceeded in an apparently normal fashion in bone marrow and thymus of PKN1[T778A] mice, however, the number of T and B cell counts were significantly higher in the lymph nodes and spleen of mutant mice in those of WT mice. After transfusion into WT recipients, EGFP-labelled PKN1[T778A] donor lymphocytes were significantly less abundant in the peripheral circulation and more abundant in the spleen and lymph nodes of recipient mice compared with EGFP-labelled WT donor lymphocytes, likely reflecting lymphocyte sequestration in the spleen and lymph nodes in a cell-autonomous fashion. PKN1[T778A] lymphocytes showed significantly lower chemotaxis towards chemokines and sphingosine 1-phosphate (S1P) than WT cells in vitro. The biggest migration defect was observed in response to S1P, which is essential for lymphocyte egress from secondary lymphoid organs. These results reveal a novel role of PKN1 in lymphocyte migration and localization.
Insights
Protein kinase N1 (PKN1) regulates lymphocyte localization. Mutant mice lacking PKN1 kinase activity show impaired lymphocyte migration, impacting T and B cell distribution in lymphoid organs and peripheral circulation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Protein kinase N1 (PKN1) is a serine/threonine kinase involved in various cellular processes.
- The precise role of PKN1 in lymphocyte trafficking and immune cell homing remains largely unexplored.
Purpose of the Study:
- To investigate the function of PKN1 kinase activity in lymphocyte migration and localization.
- To elucidate the impact of PKN1 deficiency on T and B cell distribution within the immune system.
Main Methods:
- Generation of knock-in mice with a catalytically inactive PKN1 (PKN1[T778A] mutation).
- Analysis of T and B lymphocyte counts in peripheral blood, bone marrow, thymus, lymph nodes, and spleen.
- In vitro chemotaxis assays of PKN1[T778A] lymphocytes towards chemokines and sphingosine 1-phosphate (S1P).
- Lymphocyte homing assays using EGFP-labeled cells transfused into wild-type recipients.
Main Results:
- PKN1[T778A] mice exhibited reduced peripheral blood T and B lymphocyte counts but increased counts in lymph nodes and spleen.
- Transfused PKN1[T778A] lymphocytes showed decreased peripheral circulation and increased sequestration in lymphoid organs.
- PKN1[T778A] lymphocytes displayed significantly impaired chemotaxis, particularly towards S1P, crucial for lymphocyte egress.
Conclusions:
- PKN1 kinase activity is essential for normal lymphocyte migration and localization.
- PKN1 plays a critical role in regulating lymphocyte trafficking, impacting their distribution between circulation and secondary lymphoid organs.
- Defective PKN1 function leads to impaired lymphocyte chemotaxis, highlighting a novel role in immune cell homing.
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