Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon

David Bernardo; Lydia Durant; Elizabeth R. Mann; Elizabeth Bassity; Enrique Montalvillo; Ripple Man; Rakesh Vora; Durga Reddi; Fahri Bayiroglu; Luis Fernández-Salazar; Nick R. English; Simon T.C. Peake; Jon Landy; Gui H. Lee; George Malietzis; Yi Harn Siaw; Aravinth U. Murugananthan; Phil Hendy; Eva Sánchez-Recio; Robin K. S. Phillips; Jose A. Garrote; Paul Scott; Julian Parkhill; Malte Paulsen; Ailsa L. Hart; Hafid O. Al-Hassi; Eduardo Arranz; Alan W. Walker; Simon R. Carding; Stella C. Knight

doi:10.1016/j.jcmgh.2015.08.006

Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon

David Bernardo, Lydia Durant, Elizabeth R. Mann, Elizabeth Bassity, Enrique Montalvillo, Ripple Man, Rakesh Vora, Durga Reddi, Fahri Bayiroglu, Luis Fernández-Salazar, Nick R. English, Simon T.C. Peake, Jon Landy, Gui H. Lee, George Malietzis, Yi Harn Siaw, Aravinth U. Murugananthan, Phil Hendy, Eva Sánchez-Recio, Robin K. S. PhillipsJose A. Garrote, Paul Scott, Julian Parkhill, Malte Paulsen, Ailsa L. Hart, Hafid O. Al-Hassi, Eduardo Arranz, Alan W. Walker, Simon R. Carding, Stella C. Knight

The Rowett Institute of Nutrition and Health

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

25 Citations (Scopus)

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Abstract

Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/− subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.
Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing.
Results: Colonic DC identified were myeloid (mDC, CD11c+CD123−) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3−CCR2−. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments.
Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

Original language	English
Pages (from-to)	22-39.e5
Number of pages	23
Journal	CMGH Cellular and Molecular Gastroenterology and Hepatology
Volume	2
Issue number	1
Early online date	3 Sept 2015
DOIs	https://doi.org/10.1016/j.jcmgh.2015.08.006
Publication status	Published - Jan 2016

Bibliographical note

Acknowledgments
The authors thank the Wellcome Trust Sanger Institute’s core sequencing
teams for generating sequence data.

Funding
This study was funded by the Biotechnology and Biological Sciences Research
Council, BBSRC Institute Strategic Programme for Gut Health and Food
Safety, grant BB/J004529/1; 16S rRNA gene sequencing was provided by
the Wellcome Trust (grant number WT 098051) (to P.S., J.P., A.W.W.); core
funding support from the Scottish Government Rural and Environmental
Science and Analysis Service (to A.W.W. and the Rowett Institute of Nutrition
and Health, University of Aberdeen); the Association for International Cancer
Research (AICR), Scotland, grant number 120234 (to H.O.A.); and the Junta
de Castilla y León, Spain (SAN196/VA16/07 and SAN196/VA17/07).

Keywords

CCR2
Dendritic Cells
Distal Colon
Human Gastrointestinal Tract
Proximal Colon
Microbiota

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon
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Bernardo, D., Durant, L., Mann, E. R., Bassity, E., Montalvillo, E., Man, R., Vora, R., Reddi, D., Bayiroglu, F., Fernández-Salazar, L., English, N. R., Peake, S. T. C., Landy, J., Lee, G. H., Malietzis, G., Siaw, Y. H., Murugananthan, A. U., Hendy, P., Sánchez-Recio, E., ... Knight, S. C. (2016). Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon. CMGH Cellular and Molecular Gastroenterology and Hepatology, 2(1), 22-39.e5. https://doi.org/10.1016/j.jcmgh.2015.08.006

Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon. / Bernardo, David; Durant, Lydia; Mann, Elizabeth R. et al.
In: CMGH Cellular and Molecular Gastroenterology and Hepatology, Vol. 2, No. 1, 01.2016, p. 22-39.e5.

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

Bernardo, D, Durant, L, Mann, ER, Bassity, E, Montalvillo, E, Man, R, Vora, R, Reddi, D, Bayiroglu, F, Fernández-Salazar, L, English, NR, Peake, STC, Landy, J, Lee, GH, Malietzis, G, Siaw, YH, Murugananthan, AU, Hendy, P, Sánchez-Recio, E, Phillips, RKS, Garrote, JA, Scott, P, Parkhill, J, Paulsen, M, Hart, AL, Al-Hassi, HO, Arranz, E, Walker, AW, Carding, SR & Knight, SC 2016, 'Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon', CMGH Cellular and Molecular Gastroenterology and Hepatology, vol. 2, no. 1, pp. 22-39.e5. https://doi.org/10.1016/j.jcmgh.2015.08.006

Bernardo D, Durant L, Mann ER, Bassity E, Montalvillo E, Man R et al. Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon. CMGH Cellular and Molecular Gastroenterology and Hepatology. 2016 Jan;2(1):22-39.e5. Epub 2015 Sept 3. doi: 10.1016/j.jcmgh.2015.08.006

Bernardo, David ; Durant, Lydia ; Mann, Elizabeth R. et al. / Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon. In: CMGH Cellular and Molecular Gastroenterology and Hepatology. 2016 ; Vol. 2, No. 1. pp. 22-39.e5.

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title = "Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon",

abstract = "Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/− subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing. Results: Colonic DC identified were myeloid (mDC, CD11c+CD123−) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3−CCR2−. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments. Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.",

keywords = "CCR2, Dendritic Cells, Distal Colon, Human Gastrointestinal Tract, Proximal Colon, Microbiota",

author = "David Bernardo and Lydia Durant and Mann, {Elizabeth R.} and Elizabeth Bassity and Enrique Montalvillo and Ripple Man and Rakesh Vora and Durga Reddi and Fahri Bayiroglu and Luis Fern{\'a}ndez-Salazar and English, {Nick R.} and Peake, {Simon T.C.} and Jon Landy and Lee, {Gui H.} and George Malietzis and Siaw, {Yi Harn} and Murugananthan, {Aravinth U.} and Phil Hendy and Eva S{\'a}nchez-Recio and Phillips, {Robin K. S.} and Garrote, {Jose A.} and Paul Scott and Julian Parkhill and Malte Paulsen and Hart, {Ailsa L.} and Al-Hassi, {Hafid O.} and Eduardo Arranz and Walker, {Alan W.} and Carding, {Simon R.} and Knight, {Stella C.}",

note = "Acknowledgments The authors thank the Wellcome Trust Sanger Institute{\textquoteright}s core sequencing teams for generating sequence data. Funding This study was funded by the Biotechnology and Biological Sciences Research Council, BBSRC Institute Strategic Programme for Gut Health and Food Safety, grant BB/J004529/1; 16S rRNA gene sequencing was provided by the Wellcome Trust (grant number WT 098051) (to P.S., J.P., A.W.W.); core funding support from the Scottish Government Rural and Environmental Science and Analysis Service (to A.W.W. and the Rowett Institute of Nutrition and Health, University of Aberdeen); the Association for International Cancer Research (AICR), Scotland, grant number 120234 (to H.O.A.); and the Junta de Castilla y Le{\'o}n, Spain (SAN196/VA16/07 and SAN196/VA17/07).",

year = "2016",

month = jan,

doi = "10.1016/j.jcmgh.2015.08.006",

language = "English",

volume = "2",

pages = "22--39.e5",

journal = "CMGH Cellular and Molecular Gastroenterology and Hepatology",

issn = "2352-345X",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

T1 - Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon

AU - Bernardo, David

AU - Durant, Lydia

AU - Mann, Elizabeth R.

AU - Bassity, Elizabeth

AU - Montalvillo, Enrique

AU - Man, Ripple

AU - Vora, Rakesh

AU - Reddi, Durga

AU - Bayiroglu, Fahri

AU - Fernández-Salazar, Luis

AU - English, Nick R.

AU - Peake, Simon T.C.

AU - Landy, Jon

AU - Lee, Gui H.

AU - Malietzis, George

AU - Siaw, Yi Harn

AU - Murugananthan, Aravinth U.

AU - Hendy, Phil

AU - Sánchez-Recio, Eva

AU - Phillips, Robin K. S.

AU - Garrote, Jose A.

AU - Scott, Paul

AU - Parkhill, Julian

AU - Paulsen, Malte

AU - Hart, Ailsa L.

AU - Al-Hassi, Hafid O.

AU - Arranz, Eduardo

AU - Walker, Alan W.

AU - Carding, Simon R.

AU - Knight, Stella C.

N1 - Acknowledgments The authors thank the Wellcome Trust Sanger Institute’s core sequencing teams for generating sequence data. Funding This study was funded by the Biotechnology and Biological Sciences Research Council, BBSRC Institute Strategic Programme for Gut Health and Food Safety, grant BB/J004529/1; 16S rRNA gene sequencing was provided by the Wellcome Trust (grant number WT 098051) (to P.S., J.P., A.W.W.); core funding support from the Scottish Government Rural and Environmental Science and Analysis Service (to A.W.W. and the Rowett Institute of Nutrition and Health, University of Aberdeen); the Association for International Cancer Research (AICR), Scotland, grant number 120234 (to H.O.A.); and the Junta de Castilla y León, Spain (SAN196/VA16/07 and SAN196/VA17/07).

PY - 2016/1

Y1 - 2016/1

N2 - Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/− subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing. Results: Colonic DC identified were myeloid (mDC, CD11c+CD123−) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3−CCR2−. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments. Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

AB - Background & Aims: Most knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/− subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.Methods: Paired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing. Results: Colonic DC identified were myeloid (mDC, CD11c+CD123−) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3−CCR2−. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments. Conclusions: Proximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

KW - CCR2

KW - Dendritic Cells

KW - Distal Colon

KW - Human Gastrointestinal Tract

KW - Proximal Colon

KW - Microbiota

U2 - 10.1016/j.jcmgh.2015.08.006

DO - 10.1016/j.jcmgh.2015.08.006

M3 - Article

SN - 2352-345X

VL - 2

SP - 22-39.e5

JO - CMGH Cellular and Molecular Gastroenterology and Hepatology

JF - CMGH Cellular and Molecular Gastroenterology and Hepatology

IS - 1

ER -