mTOR has distinct functions in generating versus sustaining humoral immunity

Area of Science:

• Immunology
• Cell Biology
• Molecular Signaling

Background:

• The role of mTOR signaling in plasma cell differentiation and function remains largely unknown.
• mTOR inhibition has been observed to reverse antibody-associated disease in a murine model of systemic lupus erythematosus (SLE).

Purpose of the Study:

• To investigate the role of mTOR signaling, specifically mTOR complex 1 (mTORC1), in B cell differentiation into antibody-secreting plasma cells.
• To elucidate the mechanisms by which mTOR inhibition impacts antibody production and plasma cell populations.

Main Methods:

• Induced B lineage-specific deletion of the gene encoding RAPTOR, a key component of mTORC1.
• Acute treatment of mice with rapamycin, an mTOR inhibitor.
• Analysis of plasma cell generation, antibody secretion, germinal center integrity, and protein synthesis factors (e.g., BiP).

Main Results:

• Deletion of RAPTOR or acute rapamycin treatment abrogated the generation of antibody-secreting plasma cells and obliterated germinal centers.
• mTOR perturbation led to a significant decline in serum antibodies but did not affect long-lived bone marrow plasma cell frequencies.
• mTORC1 inhibition decreased the expression of immunoglobulin-binding protein (BiP) and other protein synthesis factors.

Conclusions:

• mTOR signaling plays critical roles in both early and late phases of antibody responses and plasma cell differentiation.
• mTORC1 inhibition primarily impacts de novo antibody synthesis by affecting protein production, rather than depleting long-lived plasma cells.
• The effects of mTOR inhibition on antibody synthesis are reversible upon cessation of treatment.