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ResearchIn-Press PreviewImmunologyTransplantation
Open Access | 10.1172/JCI170191
1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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1Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
2Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
3Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America
4Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, South Bend, United States of America
5Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, United States of America
6Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America
7Immunology Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
8Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America
9Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, United States of America
10Department of Chemistry and Biochemistry and the Harper Cancer Research Ins, University of Notre Dame, Notre Dame, United States of America
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Published May 25, 2023 - More info
Bulk analysis of renal allograft biopsies (rBx) identified RNA transcripts associated with acute cellular rejection (ACR); however, these lacked cellular context critical to mechanistic understanding of how rejection occurs despite immunosuppression (IS). We performed combined single cell RNA transcriptomic and TCRα/β sequencing on rBx from patients with ACR under differing IS: tacrolimus, iscalimab, and belatacept. We found distinct CD8+ T cell phenotypes (e.g., effector, memory, exhausted) depending upon IS type, particularly within clonally expanded cells (CD8EXP). Gene expression of CD8EXP identified therapeutic targets that were influenced by IS type. TCR analysis revealed a highly restricted number of CD8EXP, independent of HLA mismatch or IS type. Subcloning of TCRα/β cDNAs from CD8EXP into Jurkat76 cells (TCR–/–) conferred alloreactivity by mixed lymphocyte reaction. Analysis of sequential rBx samples revealed persistence of CD8EXP that decreased, but were not eliminated, after successful anti-rejection therapy. In contrast, CD8EXP were maintained in treatment-refractory rejection. Finally, most rBx-derived CD8EXP were also observed in matching urine samples, providing precedent for using urine-derived CD8EXP as a surrogate for those found in the rejecting allograft. Overall, our data define the clonal CD8+ T cell response to ACR, paving the next steps to improve detection, assessment, and treatment of rejection.