Proteomic Analyses of Human Regulatory T Cells Reveal Adaptations in Signaling Pathways that Protect Cellular Identity

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 5; pp. 1046 - 1059.e6
• Main Authors: Cuadrado, Eloy, van den Biggelaar, Maartje, de Kivit, Sander, Chen, Yi-yen, Slot, Manon, Doubal, Ihsane, Meijer, Alexander, van Lier, Rene A.W., Borst, Jannie, Amsen, Derk
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-05-2018; Elsevier Limited
• Subjects: Adaptation; Autoimmune diseases; CD4 antigen; Cytokines; Destabilization; Effector cells; FOXP3; Foxp3 protein; Gene expression; Homing; Homing receptors; Immunoregulation; Inflammation; Lymphocytes; Lymphocytes T; Mass spectrometry; Metabolism; NFAT; Principal components analysis; Protein expression; Proteins; Proteomics; Receptors; regulatory T cells; Scientific imaging; Signal transduction; Signaling; Signatures; Software; STAT4; Stat4 protein; Surface markers; T cell receptors; Transcription factors; transcriptomics; regulatory T cells; proteomics; signal transduction; transcription factors; transcriptomics; STAT4; FOXP3; NFAT
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.04.008

To obtain a molecular definition of regulatory T (Treg) cell identity, we performed proteomics and transcriptomics on various populations of human regulatory and conventional CD4+ T (Tconv) cells. A protein expression signature was identified that defines all Treg cells, and another signature that defines effector Treg cells. These signatures could not be extrapolated from transcriptome data. Unique cell-biological and metabolic features in Treg cells were defined, as well as specific adaptations in cytokine, TCR, and costimulatory receptor signaling pathways. One such adaptation—selective STAT4 deficiency—prevented destabilization of Treg cell identity and function by inflammatory cytokines, while these signals could still induce critical transcription factors and homing receptors via other pathways. Furthermore, our study revealed surface markers that identify FOXP3+CD4+ T cells with distinct functional properties. Our findings suggest that adaptation in signaling pathways protect Treg cell identity and present a resource for further research into Treg cell biology.
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•Treg cell protein signatures were defined that are stable even after culture in vitro•Treg cells exhibit strategic changes in signaling pathways to protect their identity•FOXP3 protein levels exceed critical partner transcription factors in eTreg cells•Surface markers define functional heterogeneity within FOXP3+CD4+ T cells
Using high-resolution mass spectrometry and transcriptomics, Cuadrado et al. provide a molecular characterization of regulatory and conventional CD4+ T cell subsets, yielding markers to distinguish cells with different properties and insights into mechanisms that prevent regulatory T cells from exhibiting undesirable functional activities of the related but functionally antithetical conventional T cells.