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. 2022 Jun 17;11(12):3502.
doi: 10.3390/jcm11123502.

Expansion of Double-Negative T Cells in Patients before Liver Transplantation Correlates with Post-Transplant Infections

Hong Lei  1   2 , Min Tian  3 , Xiaogang Zhang  3 , Xuemin Liu  3 , Bo Wang  3 , Rongqian Wu  2 , Yi Lv  2   3
Affiliations

Expansion of Double-Negative T Cells in Patients before Liver Transplantation Correlates with Post-Transplant Infections

Hong Lei et al. J Clin Med. .

Abstract

Liver transplantation (LTx) is currently the only effective therapy for patients with end-stage liver diseases, but post-transplant infection is a key issue for morbidity and mortality. In this study, we found that pre-transplant patients with an expansion of double-negative T (DNT) cells (CD3+CD4-CD8- T cells) had an increased incidence of infections within the first 6 months after LTx. These DNT cells also negatively correlated with their CD4/CD8 ratio. Compared to patients who had no infections after LTx, these DNT cells expressed more CD25, especially in the memory compartment. The receiver operating characteristic (ROC) analysis showed that the threshold area under the ROC curve of DNT cells which could be used to distinguish LTx patients with post-transplant infections from patients without infections after LTx was 0.8353 (95% CI: 0.6591-1.000). The cut-off for the pre-LTx DNT cell level was 11.35%. Although patients with post-transplant infections had decreased levels of CD4/CD8 T cells, CD8+ T cells in these patients were more exhausted, with higher PD-1 expression and lower IFNγ secretion. The increased levels of DNT cells in patients with post-transplant infections were still observed 2 weeks after LTx, with higher proportions of memory DNT cells. In conclusion, increased levels of DNT cells in pre-LTx patients may be valuable for the prognosis of post-transplant infections, especially within the first 6 months after LTx.

Keywords: T cell exhaustion; double negative T cells; immunosuppressive therapy; infections; liver transplantation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Increased ratios of CD4+/CD8+ T cells were observed in LTx patients with post-transplant infections. (A) Ratio of CD4+/CD8+ T cells in pre-LTx patients with post-transplant infections (INF), patients without infections after LTx (NI), and healthy controls (HC) were shown individually. (B,C) The proportion of CD4+ T cells and CD8+ T cells in the two groups of patients (INF & NI) and the healthy controls were shown individually. Comparison between the three groups was undertaking through one-way ANOVA, followed by Tukey’s multiple comparison test. (INF: n = 9; NI: n = 10; HC: n = 12). * p < 0.05, ** p < 0.01.
Figure 2
Figure 2
Increased DNT cells in pre-LTx patients correlated with infections after LTx. (A) The proportion of DNT (CD3+CD4−CD8−) cells in the two groups of patients (INF & NI) and healthy controls were shown separately. (B) The receiver operating characteristic (ROC) curve of circulating DNT cells was shown to distinguish patients who developed infections from those without infections after LTx. (C) Flow cytometry gating strategy of DNT cells and T cells subsets including naïve, CM, EM, and EMRA from a representative patient. (D–G) Proportion of each cell subset in 2 patients’ groups (INF & NI) and healthy controls were shown individually. Comparison between the three groups was undertaken by one-way ANOVA, followed by Tukey’s multiple comparison test. ROC analysis of DNT cells and patients with post-transplant infections were performed using GraphPad Prism 8 (GraphPad Software, La Jolla, CA, USA). Correlation between DNT cells and CD4/CD8 ratio was performed using the Pearson correlation test. (INF: n = 9; NI: n = 10; HC: n = 12). * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Memory DNT cells in pre-LTx patients expressed more CD25 in patients with post-transplant infections. (A) The expression level of CD25 on naïve and memory DNT cells was showed from a representative patient before LTx. (B,C) Expression of CD25 on naïve and memory DNT cells in the two groups of patients (INF & NI) and healthy controls were shown individually. (INF: n = 9; NI: n = 10; HC: n = 12). * p < 0.05, *** p < 0.001.
Figure 4
Figure 4
Pre-transplant CD8+ T cells were more exhausted in patients with infections after LTx. (A–D) Percentages of CD8+ T cell subsets were similar in the two groups of patients. N: CD45RA+CD62L+ naïve T cells; CM: CD45RA−CD62L+ central-memory T cells; EM: CD45RA−CD62L− effector memory T cells; EMRA: CD45RA+CD62L− terminally differentiated effector subsets. (E) Mean Fluorescent Intensity (MFI) of PD-1 in CD8+ T cells was significantly higher in patients who developed infections after LTx, compared to those who had no infections after LTx. (F) Levels of IFNγ producing CD8+ T cells in patients with post-transplant infections were lower than those in patients who had no infections after LTx. (INF: n = 9; NI: n = 10; HC: n = 12). * p < 0.05.
Figure 5
Figure 5
Increased DNT cell levels were still observed in patients who developed post-transplant infections after LTx. (A) Patients who developed post-transplant infections still had more DNT cells 2 weeks after LTx than patients without infections. (B) Patients with post-transplant infections had more memory DNT cells 2 weeks after LTx than patients without infections. (C) Expressions of activation marker CD25 were comparable in memory DNT cells for the two groups of patients. (INF: n = 9; NI: n = 10; HC: n = 12). * p < 0.05, ** p < 0.01.
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References

    1. Kwong A., Kim W.R., Lake J.R., Smith J.M., Schladt D.P., Skeans M.A., Noreen S.M., Foutz J., Miller E., Snyder J.J., et al. OPTN/SRTR 2018 Annual Data Report: Liver. Am. J. Transplant. 2020;20:193–299. doi: 10.1111/ajt.15674. - DOI - PubMed
    1. Lizaola-Mayo B.C., Rodriguez E.A. Cytomegalovirus infection after liver transplantation. World J. Transplant. 2020;10:183–190. doi: 10.5500/wjt.v10.i7.183. - DOI - PMC - PubMed
    1. Scolarici M., Jorgenson M., Saddler C., Smith J. Fungal Infections in Liver Transplant Recipients. J. Fungi. 2021;7:524. doi: 10.3390/jof7070524. - DOI - PMC - PubMed
    1. Watt K.D., Pedersen R.A., Kremers W.K., Heimbach J.K., Charlton M.R. Evolution of causes and risk factors for mortality post-liver transplant: Results of the NIDDK long-term follow-up study. Am. J. Transplant. 2010;10:1420–1427. doi: 10.1111/j.1600-6143.2010.03126.x. - DOI - PMC - PubMed
    1. Jothimani D., Venugopal R., Vij M., Rela M. Post liver transplant recurrent and de novo viral infections. Best Pract. Res. Clin. Gastroenterol. 2020;46–47:101689. doi: 10.1016/j.bpg.2020.101689. - DOI - PMC - PubMed