Polarizing T and B Cell Responses by APC-Targeted Subunit Vaccines

Abstract

Current influenza vaccines mostly aim at the induction of specific neutralizing antibodies. While antibodies are important for protection against a particular virus strain, T cells can recognize epitopes that will offer broader protection against influenza. We have previously developed a DNA vaccine format by which protein antigens can be targeted specifically to receptors on antigen presenting cells (APCs). The DNA-encoded vaccine proteins are homodimers, each chain consisting of a targeting unit, a dimerization unit, and an antigen. The strategy of targeting antigen to APCs greatly enhances immune responses as compared to non-targeted controls. Furthermore, targeting of antigen to different receptors on APCs can polarize the immune response to different arms of immunity. Here, we discuss how targeting of hemagglutinin to MHC class II molecules increases Th2 and IgG1 antibody responses, whereas targeting to chemokine receptors XCR1 or CCR1/3/5 increases Th1 and IgG2a responses, in addition to CD8(+) T cell responses. We also discuss these results in relation to work published by others on APC-targeting. Differential targeting of APC surface molecules may allow the induction of tailor-made phenotypes of adaptive immune responses that are optimal for protection against various infectious agents, including influenza virus.

Keywords: APC targeting; T cells; Th1; Th2; antibody; influenza vaccines; vaccine.

Figure 1

Immunization with APC-targeted dimeric vaccines protect mice against influenza. (A) The vaccine molecules consist of targeting units (scFv or natural ligands), dimerization units (hinge region and C_H3 domain of human IgG3), and antigenic units [ex. influenza hemagglutinin (HA)]. (B) BALB/c mice were immunized with 25 μg DNA encoding the indicated vaccine molecules [HA from A/California/07/2009 (H1N1)] targeted toward MHC-II molecules (αMHCII-HA), chemokine receptors 1, 3, and 5 (MIP-1α-HA) or Xcr1 (Xcl1–HA). The mice were challenged 2 weeks after a single immunization with a lethal dose of influenza A/California/07/2009 (H1N1) and monitored for weight loss. All three APC-targeted vaccines induced protection against influenza, in contrast to vaccination with HA alone or NaCl. Modified with permission from Ref. (40).

Figure 2

Targeting of selected surface receptors on APC will influence the vaccine-induced Th1/Th2 polarization and antibody subtypes. (A) Illustration of the different immune responses as induced by targeting of antigen to the chemokine receptor Xcr1 (left side) or MHC-II (right side). Left side: Targeting of antigen to Xcr1 induces IFNγ-secreting CD4⁺ Th1 cells that can provide help to B cells and promote the formation of IgG2a antibodies. In addition, targeting of Xcr1 results in presentation of peptides on MHC-I molecules, and induction of strong CD8⁺ T cell responses. Right side: Targeting of antigen to MHC-II molecules induces CD4⁺ Th2 cells that secrete IL4, and that can provide help to B cells and promote the formation of IgG1 antibodies. (B) BALB/c mice were immunized with 25 μg DNA encoding the indicated vaccine molecules [HA from influenza A/Puerto Rico/8/1934 (H1N1)], and serums samples were harvested 2 or 10 weeks after a single immunization. Serum levels of HA-specific IgG1 and IgG2a antibodies were determined by ELISA against inactivated influenza A/Puerto Rico/8/1934 (H1N1). Modified with permission from Ref. (40).