B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex

Area of Science:

• Immunology
• Molecular Biology
• Autoimmunity

Background:

• The GARP-TGF-β axis is known in cancer immune evasion.
• Its role in systemic autoimmune diseases remains unclear.
• GARP (Glycoprotein A Repetitions Perforin) is a receptor for latent TGF-β.

Purpose of the Study:

• To investigate the role of the GARP-TGF-β axis in B cells and its implication in autoimmune diseases.
• To determine if B cells can express GARP and its functional consequences.

Main Methods:

• Induction of GARP-TGF-β complex on human and mouse B cells using TLR ligands (TLR4, TLR7, TLR9).
• Analysis of B cell proliferation, IgA class-switching, and antibody production.
• Generation of B cell-specific GARP knockout mice (Lrrc32 deletion).
• Assessment of spontaneous and induced autoimmune disease development in knockout mice.
• Investigation of oral tolerance induction in relation to B cell GARP expression.

Main Results:

• Activated B cells express the GARP-TGF-β complex upon stimulation with TLR ligands.
• GARP overexpression on B cells inhibits proliferation, promotes IgA class-switching, and reduces T cell-independent antibody production.
• B cell-specific deletion of Lrrc32 leads to spontaneous systemic autoimmune diseases and exacerbates lupus-like disease.
• GARP is upregulated in Peyer patch B cells more than splenic B cells.
• B cells expressing GARP are crucial for inducing oral tolerance to T cell-dependent antigens.

Conclusions:

• Cell surface GARP-TGF-β on B cells acts as a critical checkpoint for peripheral tolerance.
• Dysregulation of the GARP-TGF-β axis in B cells contributes to autoimmune disease pathogenesis.
• This study uncovers a novel mechanism involving B cell regulation of tolerance.