APOL1-risk alleles modulate T-cell receptor signaling to promote allograft rejection

Exonic variants in Apolipoprotein-L1 (G1 and G2) are linked to increased risk of kidney disease as well as kidney transplant rejection. Outside of the association of these prevalent variants with African ancestry, underpinning causal mechanisms for rejection are unknown. We investigated T-cell function using transgenic mice with physiologic expression of wild type (G0-), G1-APOL1 (G1), or G2-APOL1 (G2). Mice with either variant showed greater CD8+T-cell activation with expansion of a central memory (TCM) subset. Stimulated G1-CD8+T-cells showed enhanced proliferation and cytokine production, which reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1-mice demonstrated greater CD8+T-cell infiltration and reduced survival. Bulk transcriptome of G1-CD8+T-cells, and single-cell transcriptome of graft infiltrating TCMs, showed enrichment of canonical T-cell receptor (TCR) pathways including Ca2+-signaling. G1-CD8+T-cells demonstrated baseline ER-Ca2+ depletion followed by sustained increases in cytosolic-Ca2+ upon TCR stimulation. G1-CD8+T-cells were more sensitive to Ca2+ chelation, or store-operated Ca2+ entry inhibition, and were relatively resistant to calcineurin antagonism compared to G0-CD8+T-cells. Analogously, in a kidney transplant cohort, APOL1-variant recipients that had elevated peripheral TCMs before transplantation, developed rejection despite significantly higher tacrolimus levels vs G0/G0 recipients. In summary, we unravel an excitatory mechanism for APOL1 variants in T-cells that causally links them to kidney rejection.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2026-06-09
DOI
https://doi.org/10.1172/jci193173
Primary Topic
Renal Diseases and Glomerulopathies
Type
article
Field-Weighted Citation Impact
0.00

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article

APOL1-risk alleles modulate T-cell receptor signaling to promote allograft rejection

Mateus T. Guerra, Zeguo Sun, Joseph Craft, Hongmei Shi et al.
Journal of Clinical Investigation
Renal Diseases and Glomerulopathies
article

APOL1-risk alleles modulate T-cell receptor signaling to promote allograft rejection

Mateus T. Guerra, Zeguo Sun, Joseph Craft, Hongmei Shi, Jordan S. Pober, Irene Chernova, Ke Dong, Hiroki Mizuno, Stefan Somlo, Soichiro Nagata, Jamil Azzi, Wenzhi Song, John Y. Choi, John Pell, Madhav C. Menon, Waldemar Popik, Naoka Murakami, Shuta Ishibe, Peter S. Heeger, Anita S. Chong, Xin Tian, Zhongyang Zhang, John Cijiang He, Ian W. Gibson, Soltan Al Chaar, Barbara Franchin, Reika Ishibe, Anand Reghuvaran, E M Tanvir, Bony De Kumar, Gabriel Barsotti, Shinobu Smithson, Paolo Cravedi, Ashwani Kumar
article en

Abstract

Exonic variants in Apolipoprotein-L1 (G1 and G2) are linked to increased risk of kidney disease as well as kidney transplant rejection. Outside of the association of these prevalent variants with African ancestry, underpinning causal mechanisms for rejection are unknown. We investigated T-cell function using transgenic mice with physiologic expression of wild type (G0-), G1-APOL1 (G1), or G2-APOL1 (G2). Mice with either variant showed greater CD8+T-cell activation with expansion of a central memory (TCM) subset. Stimulated G1-CD8+T-cells showed enhanced proliferation and cytokine production, which reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1-mice demonstrated greater CD8+T-cell infiltration and reduced survival. Bulk transcriptome of G1-CD8+T-cells, and single-cell transcriptome of graft infiltrating TCMs, showed enrichment of canonical T-cell receptor (TCR) pathways including Ca2+-signaling. G1-CD8+T-cells demonstrated baseline ER-Ca2+ depletion followed by sustained increases in cytosolic-Ca2+ upon TCR stimulation. G1-CD8+T-cells were more sensitive to Ca2+ chelation, or store-operated Ca2+ entry inhibition, and were relatively resistant to calcineurin antagonism compared to G0-CD8+T-cells. Analogously, in a kidney transplant cohort, APOL1-variant recipients that had elevated peripheral TCMs before transplantation, developed rejection despite significantly higher tacrolimus levels vs G0/G0 recipients. In summary, we unravel an excitatory mechanism for APOL1 variants in T-cells that causally links them to kidney rejection.

Journal of Clinical Investigation
Meharry Medical College (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), Washington University in St. Louis (US), Yale University (US), University of Chicago (US), University of Manitoba (CA), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Defense, Yale University, Maze Therapeutics, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Good health and well-being
Openalex Percentile: Top 7%
Renal Diseases and Glomerulopathies
DOIOpen Access PDFOpenAlex
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