Phosphatase inhibitor PPP1R11 modulates resistance of human T cells toward Treg-mediated suppression of cytokine expression

Abstract

Regulatory T cells (Tregs) act as indispensable unit for maintaining peripheral immune tolerance mainly by regulating effector T cells. T cells resistant to suppression by Tregs pose therapeutic challenges in the treatment of autoimmune diseases, while augmenting susceptibility to suppression may be desirable for cancer therapy. To understand the cell intrinsic signals in T cells during suppression by Tregs, we have previously performed a global phosphoproteomic characterization. We revealed altered phosphorylation of protein phosphatase 1 regulatory subunit 11 (PPP1R11; Inhibitor‐3) in conventional T cells upon suppression by Tregs. Here, we show that silencing of PPP1R11 renders T cells resistant toward Treg‐mediated suppression of TCR‐induced cytokine expression. Furthermore, whole‐transcriptome sequencing revealed that PPP1R11 differentially regulates not only the expression of specific T cell stimulation‐induced cytokines but also other molecules and pathways in T cells. We further confirmed the target of PPP1R11, PP1, to augment TCR‐induced cytokine expression. In conclusion, we present PPP1R11 as a novel negative regulator of T cell activation‐induced cytokine expression. Targeting PPP1R11 may have therapeutic potential to regulate the T cell activation status including modulating the susceptibility of T cells toward Treg‐mediated suppression, specifically altering the stimulation‐induced T cell cytokine milieu.

Differential transcriptional and functional properties of regulatory T cells in HIV‐infected individuals on antiretroviral therapy and long‐term non‐progressors

“…The RNA‐binding protein SMN1 and protein phosphatase 1 regulatory inhibitory subunit 11 (PPP1R11) were also among the most downregulated genes. PPP1R11 is a negative regulator of cytokine expression upon T‐cell activation and might contribute to Treg polarisation 32 . Finally, the comparison between LTNP and ART subjects revealed the upregulation and downregulation of 92 and 63 transcripts in ART compared with LTNPs, respectively (Figure 1b and d, Supplementary figure 1f).…”

“…PPP1R11 is a negative regulator of cytokine expression upon T-cell activation and might contribute to Treg polarisation. 32 Finally, the comparison between LTNP and ART subjects revealed the upregulation and downregulation of 92 and 63 transcripts in ART compared with LTNPs, respectively (Figure 1b and d, Supplementary figure 1f). PCA showed that although samples in the ART and LTNP groups were different, the latter one showed two subgroups (Supplementary figure 1g).…”

TcellSubC: An Atlas of the Subcellular Proteome of Human T Cells

“…Further, we evaluated the biological response of the T cells from these donors toward stimulation by studying the expression of TCR stimulation-induced IL2 and IFNG mRNA upon 3 h of stimulation by qRT-PCR (Figure S3). IL2 and IFNG cytokine mRNA upregulation triggered by cross-linked anti-CD3/anti-CD28 stimulation of human CD4+CD25- conventional T cells, as used here, has been previously established in our laboratory to be a suitable quality control for TCR activation at relevant time points, as assessed by calcium influx and phosphorylation of downstream signaling molecules of the NFAT, NF-kB, and AP-1 pathways (34), global increase in protein phosphorylation by phosphoproteomics (22) as well as long-term functional readouts such as secretion of IL-2, IFN-γ and other cytokines as well as T cell proliferation (34, 35). The purities of isolated protein fractions were evaluated by studying the expression of established subcellular markers by Western Blot analysis (Figure 1B).…”

Transcriptional regulatory networks of circulating immune cells in type 1 diabetes: A community knowledgebase

“…Moreover, abundant evidence implicates mitogen-activated protein kinases in pathways regulating innate immunity; MAPK1/ERK, for example, has been shown to suppress NFKB signaling in endothelial cells ( Maeng et al., 2006 ). In addition, T cells depleted of PPP1R11 are resistant to Treg-mediated suppression of cytokine expression ( Joshi et al., 2019 ), and the APOBECG3 deaminase inhibits retrotransposition of retroviruses, which have been implicated in autoimmune disorders ( Esnault et al., 2005 ). Among co-nodes, NPC1 has recently been shown to be essential for degradation of STING, a well-known mediator of autoimmune responses ( Chu et al., 2021 ).…”