Dataset Information

Specialized dendritic cells induce tumor-promoting IL-10⁺IL-17⁺ FoxP3^neg regulatory CD4⁺ T cells in pancreatic carcinoma.

ABSTRACT: The drivers and the specification of CD4⁺ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T_H-program. Specifically, CD11b⁺CD103^- DC predominate in PDA, express high IL-23 and TGF-?, and induce FoxP3^neg tumor-promoting IL-10⁺IL-17⁺IFN?⁺regulatory CD4⁺ T cells. The balance between this distinctive T_H program and canonical FoxP3⁺T_REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T_H-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b⁺CD103^- DC promote CD4⁺ T cell tolerance in PDA which may underscore its resistance to immunotherapy.

SUBMITTER: Barilla RM

PROVIDER: S-EPMC6441038 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma.

Barilla Rocky M RM Diskin Brian B Caso Raul Caso RC Lee Ki Buom KB Mohan Navyatha N Buttar Chandan C Adam Salma S Sekendiz Zennur Z Wang Junjie J Salas Ruben D RD Cassini Marcelo F MF Karlen Jason J Sundberg Belen B Akbar Hashem H Levchenko Dmitry D Gakhal Inderdeep I Gutierrez Johana J Wang Wei W Hundeyin Mautin M Torres-Hernandez Alejandro A Leinwand Joshua J Kurz Emma E Rossi Juan A Kochen JAK Mishra Ankita A Liria Miguel M Sanchez Gustavo G Panta Jyoti J Loke P'ng P Aykut Berk B Miller George G

Nature communications 20190329 1

The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-β, and induce Fo ...[more]

PMID: 30926808

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Project description:CCR5 is a CC chemokine receptor involved in the migration of effector leukocytes including macrophages, NK, and T cells into inflamed tissues. Also, the role of CCR5 in CD4(+)Foxp3(+) regulatory T cell (Treg) homing has recently begun to grab attention. Japanese encephalitis (JE) is defined as severe neuroinflammation of the central nervous system (CNS) following infection with mosquito-borne flavivirus JE virus. However, the potential contribution of CCR5 to JE progression via mediating CD4(+)Foxp3(+) Treg homing has not been investigated.Infected wild-type (Ccr5(+/+)) and CCR5-deficient (Ccr5(-/-)) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, NK- and JEV-specific T cell responses were analyzed. Adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs was used to evaluate the role of Tregs in JE progression.CCR5 ablation exacerbated JE without altering viral burden in the extraneural and CNS tissues, as manifested by increased CNS infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Compared to Ccr5(+/+) mice, Ccr5(-/-) mice unexpectedly showed increased responses of IFN-?(+)NK and CD8(+) T cells in the spleen, but not CD4(+) T cells. More interestingly, CCR5-ablation resulted in a skewed response to IL-17(+)CD4(+) Th17 cells and correspondingly reduced CD4(+)Foxp3(+) Tregs in the spleen and brain, which was closely associated with exacerbated JE. Our results also revealed that adoptive transfer of sorted CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice could ameliorate JE progression without apparently altering the viral burden and CNS infiltration of IL-17(+)CD4(+) Th17 cells, myeloid-derived Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Instead, adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice resulted in increased expression of anti-inflammatory cytokines (IL-10 and TGF-?) in the spleen and brain, and transferred CCR5(+) Tregs were found to produce IL-10.CCR5 regulates JE progression via governing timely and appropriate CNS infiltration of CD4(+)Foxp3(+) Tregs, thereby facilitating host survival. Therefore, this critical and extended role of CCR5 in JE raises possible safety concerns regarding the use of CCR5 antagonists in human immunodeficiency virus (HIV)-infected individuals who inhabit regions in which both HIV and flaviviruses, such as JEV and West Nile virus, are endemic.

Dataset Information

Specialized dendritic cells induce tumor-promoting IL-10⁺IL-17⁺ FoxP3^neg regulatory CD4⁺ T cells in pancreatic carcinoma.

Publications

Specialized dendritic cells induce tumor-promoting IL-10<sup>+</sup>IL-17<sup>+</sup> FoxP3<sup>neg</sup> regulatory CD4<sup>+</sup> T cells in pancreatic carcinoma.

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