Control of the specificity of T cell-mediated anti-idiotype immunity by natural regulatory T cells.
The idiotypes of B cell lymphomas represent tumor-specific antigens. T cell responses induced by idiotype vaccination in vivo are directed predominantly against CDR peptides, whereas in vitro T cells also recognize framework-derived epitopes. To investigate the mechanisms regulating the specificity of idiotype-specific T cells, BALB/c or B10.D2 mice were immunized with mature dendritic cells loaded with H-2K(d)-restricted peptides from influenza hemagglutinin, or from shared (J region) or unique (CDR3) structures of the A20 lymphoma idiotype. Antigen-specific T cells were induced in vivo by the CDR3 and influenza epitopes, but not by the J peptide. Gene expression profiling of splenic regulatory T cells revealed vaccination-induced Treg activation and proliferation. Treg activity involved J epitope-dependent IL-10 secretion and functional suppression of peptide-specific effector T cells. Vaccination-induced in vivo proliferation of transgenic hemagglutinin-specific T cells was suppressed by co-immunization with the J peptide and was restored in CD25-depleted animals. In conclusion, Treg induced by a shared idiotype epitope can systemically suppress T cell responses against idiotype-derived and immunodominant foreign epitopes in vivo. The results imply that tumor vaccines should avoid epitopes expressed by normal cells in the draining lymph node to achieve optimal anti-tumor efficacy.
Warncke
Max
M
Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
Buchner
Maike
M
Thaller
Gudrun
G
Dodero
Anna
A
Bulashevska
Alla
A
Pfeifer
Dietmar
D
Timmer
Jens
J
Veelken
Hendrik
H
D000818:Animals; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D006183:H-2 Antigens / Q000378:metabolism; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D007130:Immunoglobulin Idiotypes / Q000276:immunology* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000276:immunology / Q000378:metabolism; D007157:Immunologic Surveillance; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; C483468:hemagglutinin, human influenza A virus