APOL1 risk alleles modulate T cell receptor signaling to promote allograft rejection
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
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
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Research Article Immunology Nephrology

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

Abstract

The exonic variants G1 and G2 in apolipoprotein-L1 (APOL1) are linked to an increased risk of kidney disease as well as kidney transplant rejection. Outside of the association of these prevalent variants with African ancestry, the underpinning causal mechanisms for rejection are unknown. We investigated T cell function using transgenic mice with physiologic expression of WT (G0), G1 APOL1 (G1), or G2 APOL1 (G2). Mice with the G1 or G2 variant showed greater CD8+ T cell activation with expansion of a central memory T cell (Tcm) subset. Stimulated G1 CD8+ T cells showed enhanced proliferation and cytokine production, which was reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1 mice demonstrated greater CD8+ T cell infiltration and worse survival. The bulk transcriptome of G1 CD8+ T cells and the 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 with G0 CD8+ T cells. Analogously, in a kidney transplant cohort, transplant recipients carrying an APOL1 risk variant (G1 or G2) who had elevated peripheral Tcms before transplantation developed rejection despite having significantly higher tacrolimus levels than recipients with the G0/G0 APOL1 genotype. In summary, we have unraveled 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

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Figure 7

Transcriptome analyses reveal enhanced calcium-mediated calcineurin/NFAT signaling in G1 CD8+ T cells.

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Transcriptome analyses reveal enhanced calcium-mediated calcineurin/NFAT...
(A) Principal component (PC) analysis of the CD8+ T cell transcriptome of G1 versus G0 BAC-Tg mice. (B) Volcano plot of significant DEGs in G1 versus G0 transcriptomes. Dashed line P = 0.05; selected Ca2+ signaling–related transcripts are highlighted. (C) Functional enrichment analyses of significant DEGs (at P < 0.01 and P < 0.05, respectively). (D) Uniform manifold approximation and projection (UMAP) of scRNA-seq of CD3+ T cells from G1 and G0 recipient allografts (n = 3 each). (E) Bubble plot shows expression of canonical T cell markers for subset annotation. Box plots show proportions of infiltrating (F) Tcms and (G) Tregs in each sample (median/IQR; whiskers represent ± 1.5 box heights). (H) Significant DEGs (P < 0.01) within each T cell subset in G1 versus G0 comparisons. (Each column represents 1 gene; red = upregulated, blue = downregulated.) (I) Volcano plot of the DEGs from infiltrating Tcms in G1 versus G0 comparisons (dashed line P = 0.01). (J) Functional enrichment analyses with the top 50 DEGs (ranked after downsampling) in Tcms. CD8_early_act, activated CD8+ T cells in the early phase; DP, CD4+/CD8+ double-positive; Prolif, proliferating cells.