Molecular switches for regulating the differentiation of inflammatory and IL-10-producing anti-inflammatory T-helper cells

Abstract

CD4 T-helper (Th) cells secret a variety of inflammatory cytokines and play critical roles in host defense against invading foreign pathogens. On the other hand, uncontrolled inflammatory responses mediated by Th cells may result in tissue damage and inflammatory disorders including autoimmune and allergic diseases. Thus, the induction of anti-inflammatory cytokine expression becomes an important "brake" to repress and/or terminate aberrant and/or unnecessary immune responses. Interleukin-10 (IL-10) is one of the most important anti-inflammatory cytokines to limit inflammatory Th cells and immunopathology and to maintain tissue homeostasis. Many studies have indicated that Th cells can be a major source of IL-10 under specific conditions both in mouse and human and that extracellular signals and cell intrinsic molecular switches are required to turn on and off Il10 expression in different Th cells. In this review, we will highlight the recent findings that have enhanced our understanding on the mechanisms of IL-10 induction in distinct Th-cell subsets, including Th1, Th2, and Th17 cells, as well as the importance of these IL-10-producing anti-inflammatory Th cells in immunity and inflammation.

Keywords: Bhlhe40; C-Maf; Cytokine expression; Immunopathology; T-cell activation; T-cell homeostasis; T-helper cell differentiation; Transcriptional regulation.

Fig. 1

IL-10-producing T-helper cells in diseases. Upon T-cell receptor engagement and co-stimulation signaling, naïve CD4 T cells differentiate into type 1 T-helper (Th1), Th2, and Th17 cells, as well as IL-10-producing anti-inflammatory peripherally derived regulatory T (pTreg) cells. Under certain conditions, Th cells also have capability to express IL-10 in addition to their effector cytokines. IL-10⁺ Th1 cells are identified in Plasmodium induced malaria, and during Leishmania, Toxoplasma, lymphocytic choriomeningitis virus (LCMV), Mycobacterium and respiratory syncytial virus (RSV) infection, as well as in inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) disease. Th1 and IL-10⁺ Th1 cells may switch between each other, and Th1 cells express low levels of IL-10R. IL-10⁺ Th2 cells are induced in helminth infection, allergy, and pregnancy disorder conditions. Both Th2 and IL-10⁺ Th2 cells express IL-10R. IL-10⁺ Th17 cells are found in neuroadapted sindbis virus and Staphylococcus aureus infection, experimental autoimmune encephalomyelitis (EAE), RA, IBD, type 1 diabetes (T1D), and dry eye disease (DED). The IL-10R-expressing Th17 cells play critical roles in inflammatory diseases

Fig. 2

Genomic regulatory elements at the Il10 locus in T-helper cells. The murine Il10 gene comprises five exons and many cis-regulatory elements, which are identified as DNase I hypersensitivity sites (DHSs). In Th cells, there are four major functional DHSs: DHS-9, DHS-transcriptional start site (DHS-TSS), DHS + 3, and DHS + 6.5. Different transcription factors bind to those sites to regulate IL-10 expression in different cell types

Fig. 3

Regulators of IL-10 expression in T-helper cells. IL-10-producing Th cells can be induced and regulated through different mechanisms which include: extracellular physical and chemical factors; cytokine and membrane proteins that trigger signaling; cytoplasmic signaling regulators; transcription factors in the nucleus. Th cells may share some common mechanism and regulators to induce IL-10 expression, such as PKCθ, c-Maf, Bhlhe40, etc. However, each Th-cell subset also has its own lineage-specific regulators for switching on and off IL-10 production