Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Sci Rep. 2020 Jan 16;10(1):493. doi: 10.1038/s41598-020-57507-8.

Abstract

Interleukin 27 (IL-27), a member of the IL-12 family, is important for T cell differentiation; however, little is known about its effect on dendritic cells (DCs). IL-27 can activate multiple signaling cascades, including the JAK/STAT pathway, and depending on the setting it can both promote and antagonize inflammatory responses. An anti-inflammatory function of IL-27 has been reported in several autoimmune diseases; however, in type 1 diabetes (T1D), an autoimmune disease where autoreactive cytotoxic T cells attack insulin-producing beta cells, IL-27 has been shown to have a dual role and contradictory effects. Here, we show impaired IL-27 signaling in a large cohort of T1D patients (n = 51) compared to age- and gender-matched healthy donors. Increased expression of the IL-27 receptor subunit IL-27Ralpha mRNA in purified myeloid DCs (mDCs), detected by gene expression microarrays was mirrored by enhanced signal transduction in T1D mDCs in response to IL-27 stimulation. Higher STAT phosphorylation in T1D patients was also accompanied by elevated expression of the inhibitory molecules PD-L1, PD-L2 and PD-1, which may suggest not only immunomodulatory mechanisms of IL-27 in T1D but also a compensatory effort of T1D dendritic cells against the ongoing inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / metabolism
  • Case-Control Studies
  • Dendritic Cells / immunology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Female
  • Gene Expression Profiling / methods*
  • Humans
  • Interleukins / genetics
  • Interleukins / metabolism
  • Male
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • IL27RA protein, human
  • Interleukins
  • MYDGF protein, human
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • STAT3 protein, human