Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts
Franco B. Mueller, … , Manikkam Suthanthiran, Thangamani Muthukumar
Franco B. Mueller, … , Manikkam Suthanthiran, Thangamani Muthukumar
Published July 11, 2019
Citation Information: JCI Insight. 2019;4(13):e128014. https://doi.org/10.1172/jci.insight.128014.
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Categories: Research Article Immunology Transplantation

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

Abstract

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell–mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

Authors

Franco B. Mueller, Hua Yang, Michelle Lubetzky, Akanksha Verma, John R. Lee, Darshana M. Dadhania, Jenny Z. Xiang, Steven P. Salvatore, Surya V. Seshan, Vijay K. Sharma, Olivier Elemento, Manikkam Suthanthiran, Thangamani Muthukumar

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Figure 8

Kidney allograft expression of mRNAs encoding calcineurin PPP3R1 and inosine-5′-monophosphate dehydrogenase 1 (IMPDH1) in TCMR and Normal.

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Kidney allograft expression of mRNAs encoding calcineurin PPP3R1 and ino...
Intragraft mRNA abundance of calcineurin isoform PPP3R1 (protein phosphatase 3 regulatory subunit B, α) (A), and IMPDH1 (B) in TCMR and Normal. In the box plots, the 2 dotted red lines represent the 95% confidence interval of the Normal group. Calcineurin, a phosphatase made of 2 proteins, CNA and CNB, cleaves phosphate from serine and threonine in proteins. CNA possesses the phosphatase enzymatic activity and binds calmodulin. CNB binds Ca2+ directly and regulates the activity of CNA. Tacrolimus acts as an immunosuppressive drug by binding to and inhibiting calcineurin. We used PPP3R1 mRNA abundance as a marker of calcineurin inhibition. Mycophenolate acts by inhibiting IMPDH, an enzyme that catalyzes the oxidation of inosine monophosphate to xanthosine monophosphate, which is the rate-limiting step in the de novo biosynthesis of guanine nucleotide. We used IMPDH1 mRNA abundance as a marker of mycophenolate action. Scatter plots depict the association between calcineurin isoform PPP3R1 and NFATC2, a key transcription factor necessary to produce the T cell proliferative cytokine IL-2 (C), between IMPDH1 and a T cell score derived by xCell (D), and between PPP3R1 and IMPDH1 (E). We used NFATC2 as a marker of the effect of calcineurin inhibition on T cells. We used T cell xCell score as a marker of the effect of mycophenolate on T cells. One patient in the TCMR group who did not receive tacrolimus is shown in red in the scatter plot.