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

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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.

Authors

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