The kidney-renal lymph node-system contributes to cross-tolerance against innocuous circulating antigen

Area of Science:

• Immunology
• Nephrology
• Cell Biology

Background:

• Soluble antigens (Ags) without inflammatory stimuli typically induce T cell tolerance in the spleen.
• The kidney's role in presenting circulating soluble Ags for T cell tolerance is not well understood.

Purpose of the Study:

• To investigate the kidney-renal lymph node (rLN) system's role in tolerogenic presentation of circulating soluble Ags.
• To elucidate the mechanism by which the kidney contributes to T cell tolerance.

Main Methods:

• Studied the filtration and concentration of soluble proteins by the kidney glomerulus and tubules.
• Investigated the uptake and transport of filtered Ags by kidney dendritic cells (kDCs) and rLN-resident DCs.
• Analyzed T cell activation, proliferation, cytokine production, lifespan, and apoptosis following Ag presentation.
• Assessed the role of kDCs by performing nephrectomy post-Ag injection.

Main Results:

• Proteins smaller than albumin are filtered by the kidney and concentrated in the tubular compartment.
• Kidney dendritic cells (kDCs) endocytose filtered Ags and transport them to rLNs.
• rLN-resident DCs internalize Ags via mannose receptor-mediated endocytosis and activate specific CD8+ T cells.
• Activated CD8+ T cells exhibit tolerogenic features: no effector cytokines, no cytotoxicity, reduced lifespan, and apoptosis.
• T cell tolerization occurs independently of kDCs, as demonstrated by nephrectomy experiments.

Conclusions:

• The kidney-renal lymph node system plays a significant role in tolerogenic presentation of circulating soluble Ags.
• This mechanism involves the kidney filtering and concentrating Ags, followed by presentation to rLN-resident DCs, inducing CD8+ T cell cross-tolerance.
• This pathway may prevent immunity against innocuous circulating proteins below albumin size.