An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells.
In humans and other mammals it is known that calcium and phosphate ions are secreted from the distal small intestine into the lumen. However, why this secretion occurs is unclear. Here, we show that the process leads to the formation of amorphous magnesium-substituted calcium phosphate nanoparticles that trap soluble macromolecules, such as bacterial peptidoglycan and orally fed protein antigens, in the lumen and transport them to immune cells of the intestinal tissue. The macromolecule-containing nanoparticles utilize epithelial M cells to enter Peyer's patches, small areas of the intestine concentrated with particle-scavenging immune cells. In wild-type mice, intestinal immune cells containing these naturally formed nanoparticles expressed the immune tolerance-associated molecule 'programmed death-ligand 1', whereas in NOD1/2 double knockout mice, which cannot recognize peptidoglycan, programmed death-ligand 1 was undetected. Our results explain a role for constitutively formed calcium phosphate nanoparticles in the gut lumen and show how this helps to shape intestinal immune homeostasis.
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Jonathan J
JJ
Powell
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Emma
E
Thomas-McKay
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Vinay
V
Thoree
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Jack
J
Robertson
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Rachel E
RE
Hewitt
Cambridge Advanced Imaging Centre, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
Jeremy N
JN
Skepper
Institute for Materials Research, SPEME, University of Leeds, Leeds LS2 9JT, UK.
Andy
A
Brown
Departamento de Ciencia de los Materiales e Ingenieria Metalúrgica y Química Inorganica, Facultad de Ciencias, Universidad de Cádiz, Campus Universitario Rio San Pedro, Puerto Real (Cádiz) 11.510, Spain.
Juan Carlos
0000000184990395
JC
Hernandez-Garrido
Department of Materials Science and Metallurgy, University of Cambridge, 27 Charles Babbage Road, Cambridge CB3 0FS, UK.
Paul A
PA
Midgley
Technische Universitaet Dresden, Fakultaet Maschinenwesen, Institut fuer Stroemungsmechanik, Dresden 01062, Germany.
Inmaculada
I
Gomez-Morilla
Ion Beam Centre, Advanced Technology Institute, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Geoffrey W
GW
Grime
1] Ion Beam Centre, Advanced Technology Institute, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK [2] Institute of Cancer Sciences, The University of Manchester, 27 Palatine Road, Withington, Manchester M20 3LJ, UK.
Karen J
KJ
Kirkby
The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
Neil A
NA
Mabbott
The Roslin Institute and Royal (Dick) School of Veterinary Sciences, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
David S
DS
Donaldson
Department of Pathology, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
Ifor R
IR
Williams
Department of Pathology, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
Daniel
D
Rios
Department of Laboratory Medicine and Pathobiology, 1 King's College Circle, Toronto M5S 1A8, Canada.
Stephen E
SE
Girardin
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Carolin T
CT
Haas
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Sylvaine F A
SF
Bruggraber
1] Department of Immunology, Erasmus MC, University Medical Centre and MS Centre ErasMS, PO Box 2040, Rotterdam 3000 CA, The Netherlands [2] Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Jon D
JD
Laman
Department of Internal Medicine IV and Institute of Medical Microbiology and Hygiene, University Medical Center, Freiburg 79106, Germany.
Yakup
Y
Tanriver
Immunoregulation Laboratory, MRC Centre for Transplantation, King's College London, Guys' Hospital, London SE1 9RT, UK.
Giovanna
G
Lombardi
Immunoregulation Laboratory, MRC Centre for Transplantation, King's College London, Guys' Hospital, London SE1 9RT, UK.
Robert
R
Lechler
1] Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK [2] Royal College of Physicians, 11 St Andrews Place, Regent's Park, London NW1 4LE, UK.
Richard P H
RP
Thompson
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, Fulbourn Road, Cambridge CB1 9NL, UK.
Laetitia C
LC
Pele
D000818:Animals; D000941:Antigens / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D002130:Calcium Phosphates / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007422:Intestines / Q000737:chemistry / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008903:Minerals / Q000276:immunology; D018832:Molecular Chaperones / Q000276:immunology; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010316:Particle Size; D010457:Peptidoglycan / Q000276:immunology*; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology*; D010710:Phosphates / Q000276:immunology*
D000941:Antigens; D002130:Calcium Phosphates; D008903:Minerals; D018832:Molecular Chaperones; D010457:Peptidoglycan; D010710:Phosphates; C020243:calcium phosphate; D002118:Calcium