Salt inducible kinases 2 and 3 are required for thymic T cell development

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Salt Inducible Kinases (SIKs) are known regulators of innate immunity, metabolism, and neuronal function.
• The specific role of SIKs in adaptive immunity, particularly T cell development, remained largely unexplored.

Purpose of the Study:

• To investigate the function of Salt Inducible Kinases (SIKs) in adaptive immunity.
• To elucidate the role of SIK isoforms in T cell development and thymic selection.

Main Methods:

• Utilized a combination of SIK knockout and kinase-inactive knock-in mouse models.
• Employed conditional knockout strategies using Vav-iCre and CD4-Cre transgenes to target SIK3 deletion in hematopoietic cells and at the DP stage of T cell development, respectively.
• Analyzed thymocyte populations, T cell development, TCR rearrangement, and selection processes.

Main Results:

• Loss of SIK1 and SIK2 activity did not impede T cell development.
• Combined deficiency of SIK2 and SIK3 in hematopoietic cells led to a severe reduction in peripheral T cells, with normal B cell numbers.
• SIK2 and SIK3 are essential for thymocyte development, impacting both positive and negative selection, evidenced by reduced thymocyte numbers and increased apoptosis in specific thymic populations.

Conclusions:

• SIK2 and SIK3 play a critical and previously unrecognized role in thymic T cell development.
• The findings suggest that SIK2 and SIK3 are vital for proper T cell maturation, influencing thymic selection processes.