The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response

Caroline L Sokol; Ryan B Camire; Michael C Jones; Andrew D Luster

doi:10.1016/j.immuni.2018.07.012

The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response

Immunity. 2018 Sep 18;49(3):449-463.e6. doi: 10.1016/j.immuni.2018.07.012. Epub 2018 Aug 28.

Authors

Caroline L Sokol¹, Ryan B Camire¹, Michael C Jones¹, Andrew D Luster²

Affiliations

¹ Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: aluster@mgh.harvard.edu.

Abstract

The migration of mature dendritic cells (DCs) into the draining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b⁺ DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b⁺ DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b⁺ DCs and its ligand CCL8, to exit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma. After allergen exposure, CD169⁺SIGN-R1⁺ macrophages in interfollicular regions produced CCL8, which synergized with CCL21 in a Src-kinase-dependent manner to promote CD301b⁺ DC migration. In CCR8-deficient mice, CD301b⁺ DCs remained in the SCS and were unable to enter the LN parenchyma, resulting in defective Th2 differentiation. We have defined a CCR8-dependent stepwise mechanism of DC-subset-specific migration through which LN CD169⁺SIGN-R1⁺ macrophages control the polarization of the adaptive immune response.

Keywords: CCL8; CCR8; Th2 differentiation; allergy; chemokines; dendritic cells; lymph node; macrophages; migration; papain.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigens, CD / metabolism
Cell Movement
Cells, Cultured
Chemokine CCL8 / metabolism
Dendritic Cells / physiology*
Disease Models, Animal
Female
Hypersensitivity / immunology*
Integrin alpha Chains / metabolism
Lymph Nodes / immunology*
Lymphocyte Activation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, CCR7 / metabolism*
Receptors, CCR8 / genetics
Receptors, CCR8 / metabolism*

Substances

Antigens, CD
Ccr7 protein, mouse
Ccr8 protein, mouse
Chemokine CCL8
Integrin alpha Chains
Receptors, CCR7
Receptors, CCR8
alpha E integrins

Abstract

Publication types

MeSH terms

Substances

Grants and funding