mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of...

Area of Science:

• Immunology
• Cellular Biology
• Molecular Signaling

Background:

• Mammalian target of rapamycin (mTOR) is critical for immune cell function, particularly CD4(+) T cells.
• The role of mTOR in CD8(+) T cell responses remains less understood.
• Semaphorins are signaling molecules with diverse biological functions.

Purpose of the Study:

• To investigate the role of SEMA4A in CD8(+) T cell activation and differentiation.
• To elucidate the underlying molecular mechanisms, focusing on mTOR signaling.
• To identify the functional receptor for SEMA4A in CD8(+) T cells.

Main Methods:

• Utilized SEMA4A knockout (SEMA4A(-/-)) mice and CD8(+) T cells.
• Assessed immune cell activation, cytokine production (IFN-γ, TNF-α), and effector molecule expression (granzyme B, perforin, FAS-L).
• Analyzed mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) activity.
• Administered recombinant Sema4A protein and identified plexin B2 as a receptor.

Main Results:

• SEMA4A(-/-) CD8(+) T cells showed impaired IFN-γ and TNF-α production and reduced effector molecule induction.
• CD8(+) T cell responses were significantly impaired in SEMA4A(-/-) mice during Listeria monocytogenes infection.
• SEMA4A deficiency led to reduced mTORC1 activity and elevated mTORC2 activity in CD8(+) T cells.
• Recombinant Sema4A protein restored IFN-γ production and mTORC1 activity; plexin B2 was identified as the functional receptor.

Conclusions:

• SEMA4A is essential for optimal CD8(+) T cell activation and differentiation.
• SEMA4A regulates CD8(+) T cell function through the activation of mTORC1.
• This study reveals a novel connection between semaphorin signaling and mTOR pathways in CD8(+) T cells.