1. ¹Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
2. ²Chung-Ang University College of Medicine, Dongjak-Gu, Seoul, South Korea
3. ³Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
4. ⁴Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
5. ⁵Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Correspondence: Dr T-C Wu, Department of Pathology, The Johns Hopkins University School of Medicine, CRB II Room 309, 1550 Orleans Street, Baltimore, MD 21231, USA. E-mail: wutc@jhmi.edu

Received 19 June 2007; Accepted 19 October 2007; Published online 14 February 2008.

Abstract

CD4⁺ T helper cells are known to play an integral role in the generation of CD8⁺ T-cell immune responses. We have previously shown that co-administration of DNA vaccines containing E6 or E7 protein of human papillomavirus 16 (HPV-16) combined with DNA encoding invariant (Ii) chain in which class II-associated Ii peptide (CLIP) region is replaced with the CD4⁺ T helper epitope, PADRE (Pan-DR-epitope) (Ii-PADRE DNA) enhanced HPV antigen-specific CD8⁺ T-cell immune responses in vaccinated mice. In the current study, we investigated the enhancement of HPV E7-specific CD8⁺ T-cell immune responses by PADRE-specific CD4⁺ T cells. We showed that intradermal administration of Ii-PADRE DNA at the same location as E7-expressing DNA is necessary to generate strong E7-specific CD8⁺ T-cell immune responses. We also showed that PADRE-specific CD4⁺ T cells generated by Ii-PADRE DNA vaccination expressed Th1 cytokine profile. Furthermore, our in vitro study demonstrated that PADRE-specific CD4⁺ T cells stimulated with PADRE-loaded dendritic cells secrete IL-2 that leads to the proliferation of E7-specific CD8⁺ T cells. Thus, our data suggest that activated PADRE-specific CD4⁺ T helper cells may be required at the vicinity of E7-specific CD8⁺ T cells where they secrete IL-2, which enhances the E7-specific CD8⁺ T-cell immune responses generated by DNA vaccination.