mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Mammalian target of rapamycin complex 1 (mTORC1) regulates cell metabolism and lymphocyte proliferation.
• Tuberous sclerosis complex (TSC), comprising TSC1 and TSC2, inhibits mTORC1.
• B cells are located in the spleen's marginal zone (MZ) and follicles; the MZ is crucial for humoral immunity.

Purpose of the Study:

• To investigate the mechanisms underlying marginal zone (MZ) B cell loss in mice lacking TSC1 in B cells (TSC1^BKO).
• To explore the role of lymphotoxin signaling and cathepsin activity in MZ B cell homeostasis.

Main Methods:

• Analysis of spleen MZ architecture in TSC1^BKO mice.
• Quantification of lymphotoxin (LTα, LTβ) and lymphotoxin receptor (LTβR) expression.
• Measurement of cathepsin activity in TSC1^BKO splenocytes.
• In vivo administration of rapamycin (mTORC1 inhibitor) and a pan-cathepsin inhibitor.

Main Results:

• TSC1^BKO mice exhibit severely impaired spleen MZ architecture and reduced MZ B cells.
• Reduced LTβR expression in spleen stroma and decreased LTα transcripts in B cells were observed.
• Elevated cathepsin activity, particularly cathepsin B, was detected in TSC1^BKO mice.
• In vivo inhibition of cathepsin restored LTβR expression, LTα mRNA levels, and MZ architecture.

Conclusions:

• TSC1 deletion in B cells leads to MZ B cell loss, associated with impaired spleen MZ architecture.
• Increased cathepsin activity, potentially linked to mTORC1 signaling, contributes to LTβR degradation and MZ B cell reduction.
• Targeting cathepsin activity represents a potential therapeutic strategy for restoring MZ B cell populations and function.