BST2/Tetherin is constitutively expressed on human thymocytes with the phenotype and function of Treg cells

Abstract

In contrast to peripheral plasmacytoid dendritic cells (pDC), thymic pDC constitutively express low levels of IFN-α. This leads to induction of ISG in medullary thymocytes, raising the question whether IFN-α may play a role in T cell development. When characterizing further differences between peripheral and thymic pDC, we found that thymic pDC have a phenotype consistent with an “activated signature” including expression of TNF-α and BST2, but no expression of ILT7. Given that BST2 is induced by IFN-α and IFN-α secretion is controlled by interaction between ILT7 and BST2, this regulatory pathway is apparently lost in thymic pDC. Further, we also show that BST2 is expressed constitutively on a subset of medullary thymocytes at the mRNA and protein level reflecting a history of IFN-α transduced signals. The majority of BST2+ thymocytes express CCR5 rendering them prevalent targets for R5-tropic HIV infection. Moreover, BST2+ thymocytes express Foxp3 and CD25, consistent with the phenotype of natural Treg cells, and exert suppressive activity as they impair the proliferation of autologous CD3+ thymocytes. Collectively, our results suggest that low levels of IFN-α secreted by thymic pDC play an important role in the development of natural Treg cells.

Dynamic changes in the regulatory T-cell heterogeneity and function by murine IL-2 mutein

“…Both C2 and C9 have high Ms4a4b expression ( Fig S7D), which modulates the activation by regulating proliferation and augmenting co-stimulation through GITR (Howie et al, 2009;Xu et al, 2010). Furthermore, C2-and C9-Tregs could be distinguished from each other, as C2-Tregs express more Nrp1 (which is expressed highly in natural Tregs [Yadav et al, 2012] and promotes Treg survival by interacting with Sema4a on Tconv cells [Delgoffe et al, 2013]), whereas C9-Tregs uniquely express interferon-response genes (Epeldegui et al, 2015) (Bst2, Tgtp2, Ifit1, and Isg15) ( Fig S8A and B).…”

The role of BST‐2/Tetherin in host protection and disease manifestation

“…Various other functions have been associated with BST-2. BST-2 plays a role in regulating the development of regulatory T (Treg) cells in the thymus [141]. BST-2 also regulates autophagy by interacting with the autophagy/mitophagy suppressor LRPPRC and preventing LRPPRC from binding to Beclin 1 and the anti-apoptotic protein Bcl-2.…”

Dynamic changes in the regulatory T cell heterogeneity and function by murine IL-2 mutein

“…Mitochondrial and pseudogenes were excluded from consideration as gene markers.T-stochastic neighbor embedding using RunTSNE() was utilized from Seurat for dimensionality-25 reduced visualization of single cell data.Single Cell TCR-seq. For samples prepared using the 5' Reagent Kit, 2 ul of amplified cDNA was set aside to amplify mouse TCRa and TCRb chains in two sequential target enrichment PCRs using custom reverse primers: 5'-TGAAGATATCTTGGCAGGTG-3' and 5'-30 TGCTCAGGCAGTAGCTATAATTGCT-3' were used for the 1 st PCR, and 5'-GATCTTTTAACTGGTACACA-3' and 5'-TTTGATGGCTCAAACAAGGA-3' were used for the 2 nd PCR. All forward primers, primer concentrations, and PCR conditions and cycles were the same as those specified in the manufacturer's protocol.…”

“…Monocle2 (2.8.0) was used to order cells according to pseudotime. To generate the input data for the analysis, we combined cells from IL-30 2M and isotype conditions, since (1) cell state classifications were determined independently of treatment and…”