A T-cell intrinsic Role for APOL1 Risk Alleles in Allograft Rejection.

Area of Science:

• Immunology
• Nephrology
• Genetics

Background:

• African Americans have a higher incidence of kidney disease, partly due to specific Apolipoprotein-L1 (APOL1) gene variants.
• The precise mechanisms by which APOL1 variants contribute to kidney disease and transplant rejection remain unclear.

Purpose of the Study:

• To investigate the functional impact of APOL1 variants (G1 and G2) on T-cell activation and their role in kidney transplant rejection.
• To elucidate the molecular pathways, particularly calcium signaling, involved in APOL1-mediated T-cell dysfunction.

Main Methods:

• Utilized transgenic mice expressing wild-type (G0) or variant (G1, G2) APOL1 to study T-cell function.
• Analyzed CD8+ T-cell activation, proliferation, cytokine production, and calcium signaling pathways.
• Examined cardiac transplant outcomes in APOL1 variant mice.
• Performed transcriptome analysis of T-cells and graft-infiltrating T cells.
• Correlated findings with a human kidney transplant cohort.

Main Results:

• Mice with APOL1 variants (G1, G2) exhibited heightened CD8+ T-cell activation, increased central memory (TCM) subset expansion, and enhanced proliferation and cytokine release.
• APOL1 variants led to increased CD8+ T-cell infiltration and reduced survival in cardiac transplant models.
• Transcriptome analysis revealed enrichment of T-cell receptor (TCR) and calcium signaling pathways in APOL1 variant T-cells.
• APOL1 variant T-cells showed altered calcium handling and sensitivity to calcium modulation drugs.
• In kidney transplant patients, APOL1 variants were associated with rejection, elevated TCMs, and resistance to standard immunosuppression.

Conclusions:

• APOL1 exonic variants confer an intrinsic excitatory T-cell phenotype, characterized by enhanced activation and altered calcium signaling.
• This T-cell dysfunction provides a causal mechanism linking APOL1 variants to increased kidney transplant rejection.
• Findings suggest potential therapeutic targets within T-cell calcium signaling pathways for managing APOL1-associated kidney disease.