Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Apr 6;9:682.
doi: 10.3389/fimmu.2018.00682. eCollection 2018.

Interleukin-10-Producing DC-10 Is a Unique Tool to Promote Tolerance Via Antigen-Specific T Regulatory Type 1 Cells

Affiliations
Free PMC article
Review

Interleukin-10-Producing DC-10 Is a Unique Tool to Promote Tolerance Via Antigen-Specific T Regulatory Type 1 Cells

Michela Comi et al. Front Immunol. .
Free PMC article

Abstract

The prominent role of tolerogenic dendritic cells (tolDCs) in promoting immune tolerance and the development of efficient methods to generate clinical grade products allow the application of tolDCs as cell-based approach to dampen antigen (Ag)-specific T cell responses in autoimmunity and transplantation. Interleukin (IL)-10 potently modulates the differentiation and functions of myeloid cells. Our group contributed to the identification of IL-10 as key factor in inducing a subset of human tolDCs, named dendritic cell (DC)-10, endowed with the ability to spontaneously release IL-10 and induce Ag-specific T regulatory type 1 (Tr1) cells. We will provide an overview on the role of IL-10 in modulating myeloid cells and in promoting DC-10. Moreover, we will discuss the clinical application of DC-10 as inducers of Ag-specific Tr1 cells for tailoring Tr1-based cell therapy, and as cell product for promoting and restoring tolerance in T-cell-mediated diseases.

Keywords: DC-10; T regulatory type 1 cells; dendritic cells; interleukin-10; tolerance.

Figures

Figure 1
Figure 1
IL-10-mediated modulation of myeloid cells. IL-10 binds to a tetrameric receptor consisting of two IL-10Rα and two IL-10Rβ subunits. 1. IL-10/IL-10R interaction leads to JAK1 and TYK2 phosphorylation and the consequent STAT3 and STAT1 phosphorylation. P-STATs, and in particular P-STAT3, dimerizes and translocates to the nucleus, where it promotes the transcription of specific molecules (i.e., SOCS3) or transcription factors (i.e., BCL3 and NFIL3), and inhibits the transport of MHC class II to the plasma membrane. 2. IL-10 signaling inhibits LPS-mediated activation of IKK that in turn prevents NF-kB-p65/p50 nuclear translocation and the expression of pro-inflammatory cytokine. In parallel, IL-10 promotes the selective NF-kB-p50/p50 nuclear translocation, which concurs in downregulating pro-inflammatory cytokine expression, and, in association with BCL3, promotes IL-10 expression. 3. IL-10 inhibits PI3K/Akt pathway that prevents LPS-mediated activation of MyD88, resulting in the inhibition of the expression of IRF-3 and IRF-8. 4. IL-10-mediated inhibition of PI3K/Akt pathway leads to GSK3β and MITF activation, responsible for the upregulation of the transcription of GPNMB. 5. IL-10 downmodulates LPS-induced expression of miR155, which directly inhibits SHIP1 and favors the negative regulation of TLR4 signaling by counteracting PI3K activity. 6. IL-10 enhances LPS-mediated induction of miR146b and miR187, which post-transcriptionally regulate mRNA encoding for TNF-α and reduce IL-6 and IL-12p40 transcription via inhibition of the transcription factor IkB. TYK, tyrosine kinase; JAK, Janus kinase; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; MyD88, myeloid differentiation primary response 88; STAT, signal transducer and activator of transcription; IKK, IkB kinase; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; GSK3β, glycogen synthase kinase 3 beta; MITF, microphthalmia-associated transcription factor; MAPK, mitogen-activated protein kinase; SHIP1, SH-2 containing inositol 5′ polyphosphatase 1; Bcl3, B-cell lymphoma 3-encoded protein; NFIL3, nuclear factor interleukin 3; TFs, unknown transcription factors; SOCS, suppressor of cytokine signaling; GPNMB, glycoprotein NMB; HO-1, heme-oxygenase-1; ILT, immunoglobulin-like transcript; IRF, interferon regulatory factor; IL-10R, IL-10 receptor.
Figure 2
Figure 2
DC-10 and cell therapy approaches. DC-10 are differentiated in vitro from CD14+ cells in the presence of GM-CSF/IL-4/IL-10. In allergy and autoimmunity, patient-derived DC-10 pulsed with the specific antigen (Ag) can be used to induce differentiation of autologous Ag-specific T regulatory type 1 (Tr1) cell products (1), or directly infused into patients (2). In hematopoietic stem cell (HSC) transplantation, patient-derived DC-10 can be used to differentiate patient-specific Tr1 cell products (3), or directly infused into transplanted patients (4). In solid organ transplantation, donor-derived DC-10 can be used to promote differentiation of donor-specific Tr1 cell products (5), or directly infused into transplanted patients (6).

Similar articles

See all similar articles

Cited by 4 articles

References

    1. Mosser DM, Zhang X. Interleukin-10: new perspectives on an old cytokine. Immunol Rev (2008) 226:205–18.10.1111/j.1600-065X.2008.00706.x - DOI - PMC - PubMed
    1. Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, Mayr G, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet (2008) 40:1319–23.10.1038/ng.221 - DOI - PubMed
    1. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med (2009) 361:2033–45.10.1056/NEJMoa0907206 - DOI - PMC - PubMed
    1. Engelhardt KR, Grimbacher B. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Curr Top Microbiol Immunol (2014) 380:1–18.10.1007/978-3-662-43492-5_1 - DOI - PubMed
    1. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukine-10 and the interleukine-10 receptor. Annu Rev Immunol (2001) 19:683–765.10.1146/annurev.immunol.19.1.683 - DOI - PubMed

Publication types

LinkOut - more resources

Feedback