Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity

Abstract

Objective Adoptive regulatory T cell (Treg) therapy is being trialled for the treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In‐depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies. Methods Through a combination of quantitative proteomic, multiparametric flow cytometry, RNA‐sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity. Results High‐dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative (CD49f − ) Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f high Treg display a pro‐inflammatory Th17‐like phenotype and accumulate in the blood of patients with UC. Dysregulation on CD49f Treg subsets in patients with UC correlate with disease activity. Conclusion Overall, our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.

A high-resolution mass spectrometry based proteomic dataset of human regulatory T cells

“…In sorting, first the viable single cells were gated to select CD3 + and CD4 + T cell population. Of them Treg CD25 high , CD127 low cells were sorted as Treg cells while CD25 − cells were sorted as Conv CD4 + T cells [10] . Low flow rates were used to increase yield through a reduction in stream abort events.…”

“…3 B). We have recently reported the flow cytometry and functional validation of CD49f in Tregs [10] . CD148 is a protein tyrosine phosphatase that regulates T cell receptor (TCR) signalling through Src family kinases (SFK), and has dual inhibitory/activatory functions and immune cell-specific patterning [11] .…”

Thymus-derived hormonal and cellular control of cancer

“…Inversely, Tregs have also been associated with improved survival in colorectal, head and neck, and esophageal cancers ( 85 , 86 ). This apparent paradoxical role of Treg may be associated with the fact that most of the studies rely on the solely detection of FoxP3 expression, which is transiently increased in activated conventional CD4 + T cells and cloud the specific identification of Treg ( 87 , 88 ).…”

Rebooting Regulatory T Cell and Dendritic Cell Function in Immune-Mediated Inflammatory Diseases: Biomarker and Therapy Discovery under a Multi-Omics Lens

“…CD49f − Tregs show increased suppressive ability and expression of inhibitory receptors, whereas CD49f high Tregs possess a proinflammatory phenotype and they are increased in the blood of IBD patients with active disease. They also suggest that the ratio CD49f high /CD49f − Tregs may constitute a useful predictor of disease activity, but this result should be validated in larger cohorts of patients [ 87 ]. Still, it is beyond doubt that more studies in the field of Treg proteomics in IMIDs are needed in order to disentangle the protein profile of these cells and identify novel Treg-specific markers and potential therapeutic targets.…”