Lymph-borne CD8α+ dendritic cells are uniquely able to cross-prime CD8+ T cells with antigen acquired from intestinal epithelial cells.
Cross-presentation of cellular antigens is crucial for priming CD8(+) T cells, and generating immunity to intracellular pathogens--particularly viruses. It is unclear which intestinal phagocytes perform this function in vivo. To address this, we examined dendritic cells (DCs) from the intestinal lymph of IFABP-tOVA 232-4 mice, which express ovalbumin in small intestinal epithelial cells (IECs). Among lymph DCs (LDCs) only CD103(+) CD11b(-) CD8α(+) DCs cross-present IEC-derived ovalbumin to CD8(+) OT-I T cells. Similarly, in the mesenteric lymph nodes (MLNs), cross-presentation of IEC-ovalbumin was limited to the CD11c(+) MHCII(hi) CD8α(+) migratory DCs, but absent from all other subsets, including the resident CD8α(hi) DCs. Crucially, delivery of purified CD8α(+) LDCs, but not other LDC subsets, into the MLN subcapsular lymphatic sinus induced proliferation of ovalbumin-specific, gut-tropic CD8(+) T cells in vivo. Finally, in 232-4 mice treated with R848, CD8α(+) LDCs were uniquely able to cross-prime interferon γ-producing CD8(+) T cells and drive their migration to the intestine. Our results clearly demonstrate that migrating CD8α(+) intestinal DCs are indispensable for cross-presentation of cellular antigens and, in conditions of inflammation, for the initial differentiation of effector CD8(+) T cells. They may therefore represent an important target for the development of antiviral vaccinations.
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
V
V
Cerovic
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
S A
SA
Houston
Department of Medical Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
J
J
Westlund
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
L
L
Utriainen
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
E S
ES
Davison
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
C L
CL
Scott
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
C C
CC
Bain
Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden.
T
T
Joeris
1] Immunology Section, Department of Experimental Medical Science, Lund University, Lund, Sweden [2] Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
W W
WW
Agace
Department of Molecular Immunology, Robert Koch-Institute, Berlin, Germany.
R A
RA
Kroczek
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
A M
AM
Mowat
Department of Medical Microbiology and Immunology, University of Gothenburg, Gothenburg, Sweden.
U
U
Yrlid
Centre for Immunobiology, Institute for Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
S W F
SW
Milling
D000818:Animals; D000941:Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D045142:Cross-Priming / Q000187:drug effects / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D008196:Lymph / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000819:agonists
D000941:Antigens; D016827:CD8 Antigens; C431698:CD8alpha antigen; D007093:Imidazoles; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007371:Interferon-gamma; D010047:Ovalbumin; C402365:resiquimod