Deficiency of Antibody-Suppressor CXCR5(+)CD8(+) T Cells (Not CD4(+) T-regs) Drive High Alloantibody Production in CCR5 KO Kidney Transplant Recipients.
AMERICAN JOURNAL OF TRANSPLANTATION(2022)
摘要
Abstract Kidney transplant (KTx) into CCR5 KO mice is an excellent model to study AMR immunobiology due to a heightened humoral response posited to be secondary to impaired CD4+Treg cell trafficking to the allograft. We have observed that adoptive cell therapy (ACT) with alloprimed CXCR5+CD8+ T cells mediates significant reduction of alloAb titer in CCR5 KO KTx recipients. We hypothesized that CXCR5+CD8+ T cells are more potent inhibitors of alloAb production than CD4+Tregs. We found that CCR5 KO recipients have significantly fewer CXCR5+CD8+ T cells (782±183 vs 2058±167 cells/mm3) and graft-infiltrating CD4+Treg cells (CD25+FoxP3+; 12.9±8.8 vs 56.2±8.8 cells/mm3) compared to WT recipients, as well as significantly greater quantity of splenic germinal center (GC; GL7+Fas+B220+) B cells (5814±436 vs 671±342 cells/mm3; all p<0.003). CCR5 KO recipient alloAb titer is significantly reduced following CXCR5+CD8+ T cell ACT (1259±436 vs 5951±404 in untreated controls; p<0.0001) but not following CD4+Treg ACT (5688±436). CXCR5+CD8+ T cells reduced splenic GC B cell (5813±589 to 4087±537; p=0.002) quantity, while CD4+Treg had no impact (6916±538/mm3). Compared to untreated controls, CD8-depletion in WT recipients led to significant increase in alloAb titer (1508±338 vs 6078±436) and GC B cells (671±436 vs 7761±430; p<0.0001 for both). CD4+Treg depletion led to increased alloAb titer (3180±436) and GC B cell quantity (4911±429; p<0.004 for both), though less pronounced than in the CD8-depleted group (both p<0.001). This suggests that CXCR5+CD8+ T cells are more potent regulators of alloAb production than CD4+Tregs and their deficiency in CCR5 KO recipients is the major driver of heightened humoral immunity and AMR following KTx. Supported by NIH R01 AI083456 (to GLB), T32 AI106704-07 and F32 AI161844 (to JLH), CA016058, UL1TR002733, the OSU Division of Transplant Surgery, and the OSU College of Medicine.
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关键词
kidney transplant,high alloantibody production,antibody-suppressor
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