Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity

Eur J Immunol. 2008 Jun;38(6):1585-97. doi: 10.1002/eji.200737966.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Bacterial Proteins / immunology
  • Bacterial Toxins / immunology
  • CD4 Antigens / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cross-Priming / immunology*
  • Dendritic Cells / immunology
  • Dendritic Cells / transplantation
  • Forkhead Transcription Factors / genetics
  • Heat-Shock Proteins / immunology
  • Hemolysin Proteins / immunology
  • Histocompatibility Antigens Class II / genetics
  • Humans
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Listeriosis / immunology
  • Lymphocyte Depletion / methods
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Ovalbumin / immunology
  • Phosphoproteins / immunology
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / microbiology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Trans-Activators / genetics
  • Vaccination
  • Viral Matrix Proteins / immunology

Substances

  • 60 kDa protein, Listeria monocytogenes
  • Antibodies, Monoclonal
  • Bacterial Proteins
  • Bacterial Toxins
  • CD4 Antigens
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • Histocompatibility Antigens Class II
  • Interleukin-2 Receptor alpha Subunit
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Phosphoproteins
  • Trans-Activators
  • Viral Matrix Proteins
  • cytomegalovirus matrix protein 65kDa
  • Ovalbumin
  • hlyA protein, Listeria monocytogenes