Gut-resident CX3CR1 hi macrophages induce tertiary lymphoid structures and IgA response in situ

Sci Immunol. 2020 Apr 10;5(46):eaax0062. doi: 10.1126/sciimmunol.aax0062. | PubMed

Balázs Koscsó¹, Sravya Kurapati^1,2, Richard R Rodrigues³, Jelena Nedjic⁴, Kavitha Gowda⁵, Changsik Shin⁵, Chetna Soni⁵, Azree Zaffran Ashraf¹, Indira Purushothaman⁶, Maryknoll Palisoc⁷, Sulei Xu⁸, Haoyu Sun⁸, Sathi Babu Chodisetti⁵, Eugene Lin¹, Matthias Mack⁹, Yuka Imamura Kawasawa¹⁰, Pingnian He⁸, Ziaur S M Rahman⁵, Iannis Aifantis⁴, Natalia Shulzhenko¹¹, Andrey Morgun³, Milena Bogunovic^12,5,13

1. Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
2. Biomedical Sciences PhD Program, Penn State University College of Medicine, Hershey, PA, USA.
3. College of Pharmacy, Oregon State University, Corvallis, OR, USA.
4. Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.
5. Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA, USA.
6. PhD Program in Anatomy at Penn State College of Medicine, Penn State University College of Medicine, Hershey, PA, USA.
7. MD/PhD Medical Scientist Training Program, Penn State University College of Medicine, Hershey, PA, USA.
8. Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA, USA.
9. Department of Internal Medicine/Nephrology, University Hospital Regensburg, Regensburg, Germany.
10. Department of Pharmacology and Biochemistry and Molecular Biology, Institute of Personalized Medicine, Penn State University College of Medicine, Hershey, PA, USA.
11. College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
12. Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA. milena.bogunovic@umassmed.edu.
13. Inflammatory Bowel Disease Center, Milton S. Hershey Medical Center, Hershey, PA, USA.

Abstract

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.

Presented By Balázs Koscsó | ORCID iD