title: Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity.
abstract: Immunization with purified antigens is a safe and practical vaccination strategy but is generally unable to induce sustained CD8(+) T cell-mediated protection against intracellular pathogens. Most efforts to improve the CD8(+) T cell immunogenicity of these vaccines have focused on co-administration of adjuvant to support cross-presentation and dendritic cell maturation. In addition, it has been shown that CD4(+) T cell help during the priming phase contributes to the generation of protective CD8(+) memory T cells. In this report we demonstrate that the depletion of CD4(+) T cells paradoxically enhances long-lasting CD8-mediated protective immunity upon protein vaccination. Functional and genetic in vivo inactivation experiments attribute this enhancement primarily to MHC class II-restricted CD4(+) regulatory T cells (Treg), which appear to physiologically suppress the differentiation process towards long-living effector memory T cells. Since, in functional terms, this suppression by Treg largely exceeds the positive effects of conventional CD4(+) T cell help, even the absence of all CD4(+) T cells or lack of MHC class II-mediated interactions on priming dendritic cells result in enhanced CD8(+) T cell immunogenicity. These findings have important implications for the improvement of vaccines against intracellular pathogens or tumors, especially in patients with highly active Treg.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Heit
authors.forename: Friedemann
authors.initials: F
authors.lastname: Gebhardt
authors.forename: Katharina
authors.initials: K
authors.lastname: Lahl
authors.forename: Michael
authors.initials: M
authors.lastname: Neuenhahn
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitz
authors.forename: Florian
authors.initials: F
authors.lastname: Anderl
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kastenmüller
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001426:Bacterial Proteins / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D051858:Forkhead Transcription Factors / Q000235:genetics; D006360:Heat-Shock Proteins / Q000276:immunology; D006460:Hemolysin Proteins / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics; D014611:Vaccination; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: C078516:60 kDa protein, Listeria monocytogenes; D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D000949:Histocompatibility Antigens Class II; D053645:Interleukin-2 Receptor alpha Subunit; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D010047:Ovalbumin; C038705:hlyA protein, Listeria monocytogenes