Exploiting dendritic cells to improve vaccine efficacy
Authors: Ralph M. Steinman, Melissa Pope
Journal: Journal of Clinical Investigation (2002)

The challenges to vaccine biology are dramatized by the current situation with an AIDS vaccine (see Letvin, this Perspective series, ref. 1). For years, data have been available on the HIV-1 genome and its proteins, as well as numerous antigens recognized by the immune system. Still, this information has not been readily translated into candidate vaccines that induce the broad and long-lasting T cell–mediated immunity thought to be necessary to protect people from acquiring AIDS (2–5). Vaccines are also lacking for many other serious infections in which T cell–mediated immunity should be protective. These include pathogens whose genomic sequences and antigenic proteins are well characterized: tuberculosis, malaria, and the herpes simplex, papilloma, Epstein-Barr, and hepatitis C viruses. In essence, the identification of foreign antigens is necessary but not sufficient for producing vaccines that are effective in the T cell sphere. Better vaccine delivery and vaccine adjuvants, or enhancers of immunity, are required (6, 7).

We propose that dendritic cell (DC) physiology should be considered and exploited in meeting each of the challenges in vaccine biology that lie ahead (see Table ​Table1).1). DCs act as nature’s adjuvants for regulating antigen-specific immunity. As antigen-presenting cells, DCs capture antigens, process them into peptides, and present them on products of the MHC to T cells. DCs are both efficient and specialized in antigen presentation, and they control the magnitude, quality, and memory of the ensuing immune response. DCs have been used successfully as cellular adjuvants in mice to elicit protective T cell–mediated immunity against pathogens and tumors (8, 9). These cells are now being used to prime and expand T cells specific for human cancers (refs. 10–12; see also Yu and Restifo, this Perspective series, ref. 13). The responding T cells include helper cells, especially Th1 CD4+ cells, which produce IFN-γ; and killer cells, especially CD8+ cytolytic T lymphocytes (CTLs), which exocytose granules rich in perforin and granzyme. New information indicates that DCs control responses by other classes of lymphocytes (B, NK, and NKT cells) and elicit T cell memory, a critical goal of vaccination.



Table 1

Challenges in vaccine biology requiring improved control of antigen presentation



Developing the capacity to harness DCs for vaccination seems particularly urgent in confronting infectious agents that, like HIV-1, pose unusual demands with respect to safety; the time-honored approach of microbial attenuation is now being set aside as vaccine biologists turn to defined antigens, poorly replicating vectors, and DNA. Although these vaccines introduce foreign microbial products, they often generate weak immunity, especially T cell–mediated immunity. Consequently, greater emphasis on underlying immunologic processes is needed, notably the strong adjuvant roles of DCs. Interestingly, as we discuss below, even the classical vaccine approach of microbial attenuation, used successfully for smallpox and measles, may have unknowingly exploited the adjuvant roles of DCs.