Dataset Information

Circulating PD-1⁺CXCR5^-CD4⁺ T cells underlying the immunological mechanisms of IgG4-related disease.

ABSTRACT:

Objective

The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1⁺CXCR5^-CD4⁺) in IgG4-related disease (IgG4-RD).

Methods

PD-1⁺CXCR5^-CD4⁺ T cells in the blood of patients with IgG4-RD (n = 53), patients with SS (n = 16) and healthy volunteers (n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed.

Results

The percentage and absolute number of PD-1⁺CXCR5^- cells within total CD4⁺ T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1⁺CXCR5^-CD4⁺ T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA)⁺ cells were enriched in PD-1⁺CXCR5^-CD4⁺ T cells, and the percentage and absolute number of GZMA⁺PD-1⁺CXCR5^-CD4⁺ T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4⁺ T cells, the percentage and absolute number of PD-1⁺CXCR5^-CD4⁺ T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids.

Conclusion

In IgG4-RD, circulating CD4⁺ T-cell populations were composed of PD-1⁺CXCR5^- cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA⁺PD-1⁺CXCR5^-CD4⁺ T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

SUBMITTER: Kamekura R

PROVIDER: S-EPMC6649940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCD4+ T cells play critical roles in the pathogenesis of IgG4-related disease (IgG4-RD). The aim of this study was to investigate the TCR repertoire of peripheral blood CD4+ T cells in IgG4-RD.MethodsThe peripheral blood was collected from six healthy controls and eight IgG4-RD patients. TCR β-chain libraries of CD4+ T cells were constructed by 5'-rapid amplification of cDNA ends (5'-RACE) and sequenced by Illumina Miseq platform. The relative similarity of TCR repertoires between samples was evaluated according to the total frequencies of shared clonotypes (metric F), correlation of frequencies of shared clonotypes (metric R), and total number of shared clonotypes (metric D).ResultsThe clonal expansion and diversity of CD4+ T cell repertoire were comparable between healthy controls and IgG4-RD patients, while the proportion of expanded and coding degenerated clones, as an indicator of antigen-driven clonal expansion, was significantly higher in IgG4-RD patients. There was no significant difference in TRBV and TRBJ gene usage between healthy controls and IgG4-RD patients. The complementarity determining region 3 (CDR3) length distribution was skewed towards longer fragments in IgG4-RD. Visualization of relative similarity of TCR repertoires by multi-dimensional scaling analysis showed that TCR repertoires of IgG4-RD patients were separated from that of healthy controls in F and D metrics. We identified 11 IgG4-RD-specific CDR3 amino acid sequences that were expanded in at least 2 IgG4-RD patients, while not detected in healthy controls. According to TCR clonotype networks constructed by connecting all the CDR3 sequences with a Levenshtein distance of 1, 3 IgG4-RD-specific clusters were identified. We annotated the TCR sequences with known antigen specificity according to McPAS-TCR database and found that the frequencies of TCR sequences associated with each disease or immune function were comparable between healthy controls and IgG4-RD patients.ConclusionAccording to our study of CD4+ T cells from eight IgG4-RD patients, TCR repertoires of IgG4-RD patients were different from that of healthy controls in the proportion of expanded and coding degenerated clones and CDR3 length distribution. In addition, IgG4-RD-specific TCR sequences and clusters were identified in our study.

Project description:Latent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103+ and CD103- CD4 T cells from the blood and rectum of HIV-negative (HIV-) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV+) individuals. Like gut CD4+ T cells, circulating CD103+ cells harbored more HIV DNA than did CD103- cells but transcribed less HIV RNA per provirus. Circulating CD103+ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103- cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103+ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, "latent" infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103+ CD4+ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103+ T cells share a cellular transcriptome that more closely resembles that of CD4+ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4+ or circulating CD103+ T cells from circulating CD103- T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.

Dataset Information

Circulating PD-1⁺CXCR5^-CD4⁺ T cells underlying the immunological mechanisms of IgG4-related disease.

Objective

Methods

Results

Conclusion

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Circulating PD-1+CXCR5-CD4+ T cells underlying the immunological mechanisms of IgG4-related disease.

Objective

Methods

Results

Conclusion

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Circulating PD-1⁺CXCR5^-CD4⁺ T cells underlying the immunological mechanisms of IgG4-related disease.