Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

Chen Varol; Alexandra Vallon-Eberhard; Eran Elinav; Tegest Aychek; Yami Shapira; Hervé Luche; Hans Jörg Fehling; Wolf Dietrich Hardt; Guy Shakhar; Steffen Jung

doi:10.1016/j.immuni.2009.06.025

Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

Chen Varol, Alexandra Vallon-Eberhard, Eran Elinav, Tegest Aychek, Yami Shapira, Hervé Luche, Hans Jörg Fehling, Wolf Dietrich Hardt, Guy Shakhar, Steffen Jung^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

590 Scopus citations

Abstract

The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103⁺ CX₃CR1^- lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b⁺ CD14⁺ CX₃CR1⁺ lpDCs were derived from grafted Ly6C^hi but not Ly6C^lo monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX₃CR1⁺ lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-α-secreting CX₃CR1⁺ lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.

Original language	English
Pages (from-to)	502-512
Number of pages	11
Journal	Immunity
Volume	31
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2009.06.025
State	Published - 18 Sep 2009
Externally published	Yes

Keywords

CELLIMMUNO
MOLIMMUNO

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10.1016/j.immuni.2009.06.025

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title = "Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions",

abstract = "The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103+ CX3CR1- lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b+ CD14+ CX3CR1+ lpDCs were derived from grafted Ly6Chi but not Ly6Clo monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX3CR1+ lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-α-secreting CX3CR1+ lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.",

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author = "Chen Varol and Alexandra Vallon-Eberhard and Eran Elinav and Tegest Aychek and Yami Shapira and Herv{\'e} Luche and Fehling, {Hans J{\"o}rg} and Hardt, {Wolf Dietrich} and Guy Shakhar and Steffen Jung",

note = "Funding Information: We thank A. Mahler and the Jung laboratory for critical reading of the manuscript and are grateful to Y. Chermesh and O. Amram for animal husbandry. We thank Z. Eshhar and Z. Halpern for establishing the endoscopy suite, B. Reizis for sharing his CD11c-Cre mice, N. Shpigel for providing Tnf −/− mice, and M. Manz for providing Flt3 −/− BM. We are grateful to V. Temper, Hadassah-Hebrew University Medical Center, for Salmonella typing and E. Ariel and A. Sharp for help with flow cytometry. This work was supported by the Israel Science Foundation, the MINERVA foundation, and the Fritz Thyssen Stiftung (S.J.). A.V.-E. was supported by the Association of the Swiss Friends of the Weizmann Institute. S.J. is the incumbent of the Pauline Recanati Career Development Chair. ",

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doi = "10.1016/j.immuni.2009.06.025",

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AU - Varol, Chen

AU - Vallon-Eberhard, Alexandra

AU - Elinav, Eran

AU - Aychek, Tegest

AU - Shapira, Yami

AU - Luche, Hervé

AU - Fehling, Hans Jörg

AU - Hardt, Wolf Dietrich

AU - Shakhar, Guy

AU - Jung, Steffen

N1 - Funding Information: We thank A. Mahler and the Jung laboratory for critical reading of the manuscript and are grateful to Y. Chermesh and O. Amram for animal husbandry. We thank Z. Eshhar and Z. Halpern for establishing the endoscopy suite, B. Reizis for sharing his CD11c-Cre mice, N. Shpigel for providing Tnf −/− mice, and M. Manz for providing Flt3 −/− BM. We are grateful to V. Temper, Hadassah-Hebrew University Medical Center, for Salmonella typing and E. Ariel and A. Sharp for help with flow cytometry. This work was supported by the Israel Science Foundation, the MINERVA foundation, and the Fritz Thyssen Stiftung (S.J.). A.V.-E. was supported by the Association of the Swiss Friends of the Weizmann Institute. S.J. is the incumbent of the Pauline Recanati Career Development Chair.

PY - 2009/9/18

Y1 - 2009/9/18

N2 - The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103+ CX3CR1- lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b+ CD14+ CX3CR1+ lpDCs were derived from grafted Ly6Chi but not Ly6Clo monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX3CR1+ lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-α-secreting CX3CR1+ lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.

AB - The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103+ CX3CR1- lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b+ CD14+ CX3CR1+ lpDCs were derived from grafted Ly6Chi but not Ly6Clo monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX3CR1+ lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-α-secreting CX3CR1+ lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.

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ER -

Intestinal Lamina Propria Dendritic Cell Subsets Have Different Origin and Functions

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