Immune mechanisms of protection: can adjuvants rise to the challenge?

Abstract

For many diseases vaccines are lacking or only partly effective. Research on protective immunity and adjuvants that generate vigorous immune responses may help generate effective vaccines against such pathogens.

Figure 1

Activation and differentiation of T lymphocytes. Dendritic cells (DCs) take up antigen delivered either by an infectious pathogen or by a vaccine (stage 1). DCs are activated by conserved components of pathogens binding to pattern recognition receptors (PRRs) that induce the expression of co-stimulatory molecules and the release of inflammatory cytokines. Vaccines that do not contain intrinsic adjuvants are delivered with added adjuvants, such as aluminum salts, that also activate inflammatory pathways. DCs degrade the antigen into peptides that are returned to the cell surface on MHC molecules and presented to CD8 and CD4+ T cells - antigen being presented to CD8+ T cells by MHC class I molecules, and to CD4+ T cells on MHC class II molecules (stage 2). T cells also require signals provided by the co-stimulatory molecules and inflammatory cytokines to be fully activated. Activation results in cell proliferation (stage 3) and effector cell differentiation (stage 4). CD4+ T cells can make cytokines that activate innate immune cells (such as macrophages and neutrophils) to kill pathogens. Activated CD4+ T cells can also provide help to B cells, expressing the cell-surface and soluble mediators required for the production of high-affinity class switched antibody. Effector CD8+ T cells can kill infected cells by releasing cytotoxic granules or can activate other cell types by the release of inflammatory cytokines.

Figure 2

CD4+ T helper subsets. CD4+ T cells can differentiate into different subsets depending on the cytokine milieu present during T cell activation. T_H1 cells, activated in the presence of IL-12 and IL-18 produced by activated DCs, make IFNγ, which is important in activating macrophages to kill intracellular bacteria, such as M. tuberculosis. IL-4 made by T_H2 cells activates macrophages to expel parasites (the cellular source of the IL-4 that promotes T_H2 development is currently poorly defined). T follicular (Tfh) cells can make the canonical cytokines that T_H1 or T_H2 cells produce, but they also make IL-21 and express cell-surface molecules, such as CD40 ligand and inducible T cell co-simulator (ICOS), that are required for effective B cell responses and production of high-affinity, class-switched antibodies. The more recently described T_H17 cells can produce IL-17 and IL-22 and are generated in the presence of IL-6 and TGFβ. IL-17 and IL-22 are important for promoting the influx of neutrophils to inflamed sites and the production of antimicrobial peptides, respectively. T_H17 cells are thought to be important in defense against extracellular bacteria and fungi. Activated T cells can also differentiate into regulatory T cells (Tregs) in the presence of TGFβ and/or retinoic acid (RA). These cells can inhibit and control immune responses to prevent excessive inflammation through cell-surface molecules (such as CTLA-4) or cytokines, such as IL-10.