Efficient T cell activation via a Toll-Interleukin 1 Receptor-independent pathway.
Here, we describe a previously unrecognized pathway for activation of antigen-specific adaptive immune responses that was independent of Toll-Interleukin 1 Receptor signaling and directed toward detection of antigens expressed by apoptotic cells. This pathway is represented within Flt-3 Ligand-derived dendritic cells (DCs) that represent immature lymphoid DCs, but not within GM-CSF-treated bone marrow-derived dendritic cells. Exposure of these DCs to apoptotic cells resulted in production of type I interferon and favored the development of cytotoxic T cell responses. The N-Ethyl-N-Nitrosourea-induced germline mutation 3d (Unc3b1(3d/3d)) abolished both MHC class I and II responses elicited by this pathway, whereas a null allele of Cd36 selectively abolished class II responses. We propose that this mode of adaptive immune activation evolved to permit the sensitive detection of intracellular microbial infections, particularly viral infections, which frequently induce apoptotic cell death, but may also be important in transplantation, autoimmunity, and vaccine development.
Janssen
Edith
E
Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121.
Tabeta
Koichi
K
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037.
Barnes
Michael J
MJ
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037.
Rutschmann
Sophie
S
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037.
McBride
Sara
S
Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121.
Bahjat
Keith S
KS
Cerus Corporation, Concord, California 94520.
Schoenberger
Stephen P
SP
Laboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121.
Theofilopoulos
Argyrios N
AN
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037.
Beutler
Bruce
B
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037.
Hoebe
Kasper
K
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037. Electronic address: khoebe@scripps.edu.
D000818:Animals; D017209:Apoptosis; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D007239:Infections / Q000276:immunology; D007370:Interferon Type I / Q000378:metabolism; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017472:Receptors, Interleukin-1 / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051193:Toll-Like Receptors / Q000502:physiology
D018955:CD36 Antigens; D007370:Interferon Type I; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; C084881:flt3 ligand protein