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Research Highlights

Yu, Shuangjin; Luo, Xunrong

doi: 10.1097/TP.0000000000002789
In View: Research Highlights
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Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC.

Received 7 May 2019.

Accepted 7 May 2019.

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Generation and Persistence of Human Tissue-resident Memory T Cells in Lung Transplantation

Snyder ME, Finlayson MO, Connors TJ, et al. Sci Immunol. Published online March 2019.

Persistence of donor-derived passenger leukocytes in transplanted solid organs has been variably associated with allograft pathology1 or allograft protection,2 depending on the type of organ transplanted. Specifically, resident memory T cells (TRM) generated in tissues after local antigen or infectious pathogen exposures may contribute to tissue inflammation or immunomodulation after transplantation. However, the fate of tissue-resident TRM cells of donor origin or differentiation of TRM of recipient origin in situ following transplantation remains elusive.

Snyder et al3 took advantage of human leukocyte antigen-mismatched lung transplant donor-recipient pairs studying kinetics and phenotype of donor and recipient TRM cells in lung allografts and correlated their presence with measurable clinical outcomes. The human leukocyte antigen mismatch allowed them to precisely distinguish and track recipient cells after lung transplantation.

The authors found that donor-derived TRM cells persisted in lung allografts (bronchioalveolar lavage fluid) for the entire sampling period of 12–15 months, but quickly dissipated in recipient peripheral blood by 2 months posttransplantation. Donor-derived TRM cells in lung allografts were predominantly CD8 T cells expressing canonical TRM markers CD69, CD103, and CD49a. In contrast, TRM cells of recipient origin initially expressed very low levels of such TRM markers (at 2–4 wk after transplantation), but over time gradually increased their expressions of CD69 and CD103, eventually to levels comparable with those of graft-infiltrating donor TRM cells, suggesting their de novo differentiation. Snyder et al further used single-cell RNA sequencing analysis of graft-infiltrating TRM cells from 2 lung allografts. This analysis revealed that donor T cells comprised 2 TRM-like subsets with varying levels of expression of TRM-associated genes: 1 TRM subset expressed genes associated with T cell effector function suggesting the maturity of this subset, whereas the other TRM subset expressed genes associated with cell differentiation and fate determination suggesting their ongoing differentiation. Recipient T cells comprised a similar differentiating TRM-like subset suggesting their in situ differentiation over time, as well as a non-TRM population expressing high levels of genes characteristic of effector memory T cells (TEM). Immunofluorescence imaging of transbronchial biopsies revealed a peribronchiolar distribution of donor TRM cells in comparison to a broader distribution of recipient TRM cells. Lastly, the persistence of donor TRM cells was found to be associated with a lower incidence and severity of primary graft dysfunction and acute cellular rejection and appeared to provide superior protection against bacterial infections.

This study demonstrates the potential protective role of persistent donor TRM cells in lung allograft function and provides insights to recipient TRM differentiation and function. Future research targeting1 donor TRM persistence for promoting long-term lung allograft survival and2 dissecting the role of other donor-derived non–T hematopoietic cells in lung allograft function will be of significant interest.

1. Win TS, Rehakova S, Negus MC, et al. Donor CD4 T cells contribute to cardiac allograft vasculopathy by providing help for autoantibody production. Circ Heart Fail. 2009;2:361–369.

2. Zuber J, Shonts B, Lau SP, et al. Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome. Sci Immunol. 2016;1.

3. Snyder ME, Finlayson MO, Connors TJ, et al. Generation and persistence of human tissue-resident memory T cells in lung transplantation. Sci Immunol. 2019;4.

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A Clinically Meaningful Metric of Immune Age Derived from High-dimensional Longitudinal Monitoring

Alpert A, Pickman Y, Leipold M, et al. Nat Med. Published online March 2019.

Immunological senescence has been associated with many chronic diseases of older age.1 However, quantifying immunological aging at an individual level and elucidating the dynamics of this process have been difficult. Previous studies of low dimensional immune components and short durations of tracking have not been able to capture the complexity and variability of this process.

Alpert et al2 designed a 9-year longitudinal study of 135 healthy adults using a comprehensive “omics” approach including cellular phenotyping, cytokine responses, and gene expression to quantify the aging of the human immune system. Out of the 135 subjects, 72 were old adults aged between 60 and 96 years, and 63 were young adults between 20 and 31 years old. Of these, a smaller subset (15 old adults and 3 young adults) was analyzed together annually for deep cellular phenotyping to provide a “snapshot” that is free from year-to-year technical variations. In both, the “snapshot” cohort and the large cohort, changes of individual immune cell subsets were dictated by individual baselines rather than by age itself. Moreover, changes were highly variable among individuals. However, a negative correlation was observed between annual changes of cell subsets and baseline cellular frequencies. This observation suggested that individuals with high frequencies of cell subsets decreased their levels over time, whereas those with lower frequencies increased their levels, with a tendency of both extremes to converge toward an intermediate point, where the cell subset’s levels are most stable. Using a diffusion-pseudo-time algorithm together with cellular phenotyping, cytokine responses, and gene expressions for the entire study cohort, the authors were able to construct an immune profile trajectory that represented the dynamics of immune cellular aging for healthy adults. Interestingly, immune profiles on the trajectory of young versus old adults suggested stability of the younger adults’ profile compared with older adults. Subsequently, the authors created a numeric score termed “IMM-AGE” on the basis of comprehensive immune-age metrics. To associate the IMM-AGE score with clinically significant outcomes, the authors resorted to the Framingham Heart Study which had >2000 participants in whom gene expression data were collected. There, they identified a gene set of 57 genes whose expression changed along the immune cellular aging trajectory, and significantly and consistently correlated with the IMM-AGE score, therefore allowing assignment of an approximate IMM-AGE score based on the expression of this gene set to each participant of the Framingham Heart Study. Using such an assignment, they found that males exhibited significantly higher IMM-AGE scores compared with females, suggesting a sex-specific immune aging. Of additional relevance, a higher IMM-AGE score correlated with an increased prevalence of cardiovascular diseases. Lastly, the IMM-AGE score was >500-fold more significant than the DNA methylation age in its association with patient survival, highlighting the pivotal role of immune aging in survival.

This interesting and relevant study suggests the IMM-AGE score as a useful tool for future studies charactering immune-aging initiation and may help to identify targets preventing early immune aging.

1. Nikolich-Žugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 2018;19:10–19.

2. Alpert A, Pickman Y, Leipold M, et al. A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat Med. 2019;25:487–495.

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