{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T02:12:51Z","timestamp":1792548771705,"version":"4.5.0"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":55,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21AI178705"],"award-info":[{"award-number":["R21AI178705"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.S. Department of Defense","award":["HT94252310441"],"award-info":[{"award-number":["HT94252310441"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK122164,R01DK132274"],"award-info":[{"award-number":["R01DK122164,R01DK132274"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.S. Department of Defense","award":["HT94252310454"],"award-info":[{"award-number":["HT94252310454"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32 AI155387"],"award-info":[{"award-number":["T32 AI155387"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation with expansion of a central memory T cell (Tcm) subset. Stimulated G1 CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells showed enhanced proliferation and cytokine production, which was reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1 mice demonstrated greater CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and worse survival. The bulk transcriptome of G1 CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and the single-cell transcriptome of graft-infiltrating Tcms showed enrichment of canonical T cell receptor (TCR) pathways including Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling. G1 CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells demonstrated baseline ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    depletion followed by sustained increases in cytosolic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    upon TCR stimulation. G1 CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells were more sensitive to Ca\n                    <jats:sup>2+<\/jats:sup>\n                    chelation, or store-operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry inhibition, and were relatively resistant to calcineurin antagonism compared with G0 CD8\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>\n                  <jats:p>We show that APOL1 variants promote CD8+T-cell activation via Ca2+ signaling, causally explaining their link to kidney rejection.<\/jats:p>","DOI":"10.1172\/jci193173","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T16:01:11Z","timestamp":1781020871000},"source":"Crossref","is-referenced-by-count":1,"title":["APOL1 risk alleles modulate T cell receptor signaling to promote allograft rejection"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9641-2445","authenticated-orcid":true,"given":"John","family":"Pell","sequence":"first","affiliation":[{"name":"Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut, 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