Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10–dependent ILT4/HLA-G pathway

Gregori, Silvia; Tomasoni, Daniela; Pacciani, Valentina; Scirpoli, Miriam; Battaglia, Manuela; Magnani, Chiara F.; Hauben, Ehud; Roncarolo, Maria Grazia

doi:10.1182/blood-2009-07-234872

Cited by 485 publications

(584 citation statements)

References 54 publications

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“…Also, HLA-G peptide vaccine would not be suitable for autoimmune patients because it could aggravate their disease in instances where HLA-G is expressed. 25 Homologous sequences very similar to HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] were found on the classical MHC-I HLA-A, -B and -C molecules (Table S1). Nevertheless, the HLA-G 26-40 -specific CD4 C T cells did not crossreact with these analogous peptides.…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Fig. 2B, the antigen response of all four CD4 C T cell clones was markedly blocked by the anti-HLA-DR mAb L243, but not by anti-HLA class I mAbs W6/32, indicating that HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was presented in the context of HLA-DR. Subsequently, a panel of mouse fibroblasts (L-cells) transfected with individual HLA-DR were used as antigen-presenting cells (APCs) to facilitate the identification of the specific DR allele.…”

Section: In Vitro Induction Of Hla-g-specific Cd4 C T Cell Responsesmentioning

confidence: 99%

“…4A, the HLA-G-specific CD4 C T cell clones directly recognized the HLA-DR subtype-matched tumor cells expressing HLA-G when the cell lines were treated with IFNg (Lu65, did not have to be treated with IFNg, to be recognized by the CD4 C T cell clones). The T cell response against the tumor cells was effectively inhibited by anti-HLA-DR mAb, indicating that HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was presented in the context of HLA-DR. Treatment with 5-AZA increased the T cell responses to the HLA-G-expressing tumors except for Lu65 (Fig.…”

Section: Hla-g Tumor Expression Is Enhanced By Ifng and Dna Methyltramentioning

confidence: 99%

“…Next, we determined the HLA class II molecules presenting HLA-G [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] to the four CD4 C T cell clones. We first evaluated the capacity of anti-HLA-DR mAbs (or anti-class I mAbs, as negative control) to inhibit T cell responses to peptide-pulsed autologous PBMCs.…”

Section: In Vitro Induction Of Hla-g-specific Cd4 C T Cell Responsesmentioning

confidence: 99%

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Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

et al. 2016

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(2016) Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy, OncoImmunology, 5:6, e1169356 ABSTRACTTumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4 C helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8 C cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G 26-40 was effective in eliciting tumor-reactive CD4 C T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2 0 -deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G 26-40 -specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers.

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Section: Discussionmentioning

confidence: 99%

Section: In Vitro Induction Of Hla-g-specific Cd4 C T Cell Responsesmentioning

confidence: 99%

Section: Hla-g Tumor Expression Is Enhanced By Ifng and Dna Methyltramentioning

confidence: 99%

Section: In Vitro Induction Of Hla-g-specific Cd4 C T Cell Responsesmentioning

confidence: 99%

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Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

et al. 2016

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“…7 A subset of IL-10-producing DCs is a critical factor for Tr1 (CD4 þ IL-10 þ ) cell differentiation. 12 The differentiation and function of DCs are controlled by intracellular signaling networks, such as the TLR (Toll-like receptor)/MyD88 (myeloid differentiation factor 88) signaling pathway. NF-kB is a central regulator of these immune responses, and it induces the expression of many cytokine genes.…”

Section: Intruductionmentioning

confidence: 99%

TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7

Song

Zhang

et al. 2012

Genes Immun

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The alterations induced in dendritic cells (DCs) in the cancer microenvironment have not been extensively explored. We found that the tumor-associated factor TGF-b may selectively upregulate the expression of miR-27a via the SP1 transcription factor. Importantly, miR-27a altered the activity of NF-kB and MAPKs (mitogen-activated protein kinases) p38, JNK (c-Jun N-terminal kinases) and ERK (extracellular signal-regulated kinase 1/2). It influences the production of proinflammatory cytokines by targeting TAB3, p38 MAPK, MAP2K4 and MAP2K7. As a consequence, miR-27a hampered the DC-mediated differentiation of Th1 and Th17 cells in vitro and in vivo, but it promoted the DC-mediated accumulation of Tr1 (CD4 þ IL-10 þ ) and Treg (CD4 þ CD25 þ Foxp3 þ ) cells in vivo. The repeated infusion of miR-27a-engineered DCs into tumor tissues accelerated tumor growth, indicating that miR-27a is a potential target for tumor immunotherapy.

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Leveraging current insights on IL‐10‐producing dendritic cells for developing effective immunotherapeutic approaches

Morali,

Giacomello,

Vuono

et al. 2024

FEBS Letters

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Dendritic cells (DC) are professional antigen‐presenting cells involved in promoting and controlling immune responses. Different subsets of DC, named tolerogenic (tol)DC, play a critical role in the maintenance of tissue homeostasis and in fostering tolerance. These unique skills make tolDC especially attractive for strategies aimed at re‐establishing/inducing tolerance in immune‐mediated conditions. The generation of potent tolDC in vitro from peripheral blood monocytes has seen remarkable advancements. TolDC modulate T cell dynamics by favoring regulatory T cells (Tregs) and curbing effector/pathogenic T cells. Among the several methods developed for in vitro tolDC generation, IL‐10 conditioning has been proven to be the most efficient, as IL‐10‐modulated tolDC were demonstrated to promote Tregs with the strongest suppressive activities. Investigating the molecular, metabolic, and functional profiles of tolDC uncovers essential pathways that facilitate their immunoregulatory functions. This Review provides an overview of current knowledge on the role of tolDC in health and disease, focusing on IL‐10 production, functional characterization of in vitro generated tolDC, molecular and metabolic changes occurring in tolDC induced by tolerogenic agents, clinical applications of tolDC‐based therapy, and finally new perspectives in the generation of effective tolDC.

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Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10–dependent ILT4/HLA-G pathway

Cited by 485 publications

References 54 publications

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy

TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7

Leveraging current insights on IL‐10‐producing dendritic cells for developing effective immunotherapeutic approaches

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