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Publications of the Week

Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction

By November 15, 2019No Comments

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This week we profile a recent publication in Frontiers in Immunology from the laboratory of
Dr. Wilfred Jeffries (lab group pictured above) at the Michael Smith Labs.

What is the significance of the findings in this publication?

In order to respond to foreign invaders and emerging cancers, specific cells of the immune system rely on a calcium current conveyed across their cell surface membranes to drive signals inside the immune cell when they engage and are challenged by pathogens. L-type calcium channels expressed in all mammals have traditionally been described in electrically excitable cells such as neuronal and muscle cells.

However, more recently we demonstrated that L-type calcium channels play a critical role in forming the immune system. In our current publication, we demonstrate how a mutation in such an L-type calcium channel in mice leads to significant dysfunction of their effector T lymphocytes.

T lymphocytes form part of the adaptive arm of the immune system and function to fight infections and cancers in both humans and mice. Yet, T lymphocytes in mice deficient in specific L-type calcium channels fail to produce an adequate calcium signal when stimulated. Instead, deficient mice produce effector and memory T lymphocytes expressing high levels of exhaustion markers on their cell surfaces. These markers arise during chronic infections and lead to a loss of the T lymphocyte’s ability to fight challenges by pathogens.

Our findings, therefore, demonstrate that the calcium current mediated by L-type calcium channels is essential to the fidelity of the function of T lymphocytes and establish the physiological importance of L-type calcium channels in maintaining a nimble and effective immune system for fighting infections and cancers.

What are the next steps for this research?

We are currently working on the description of three siblings who all have a mutation in an L-type calcium channel. As children, all three patients experienced chronic infections implying they are immunocompromised. Our findings have clinical relevance for understanding how to reverse immune deficiencies and fight infections and emerging cancers.

This research was funded by:

This research is made possible by donations to the Jefferies Laboratory through the Sullivan Foundation at Vancouver General Hospital. First author, Franz Fenninger, was the recipient of a DOC Fellowship of the Austrian Academy of Science and the Dmitry Apel Memorial Scholarship. Shawna Stanwood was the recipient of the John Richard Turner Fellowship in Microbiology and Hitesh Arora was the recipient of a Centre for Blood Research Graduate Student Award. This research was also supported by grants to Professor Wilfred Jefferies from the Canadian Institutes of Health Research.

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