Abstract
The type of immune response is critical for successful protection and typically determined by pathogen-associated danger molecules. In contrast, protein antigens are usually regarded as passive target structures. Here, we provide evidence that the structure of the antigen can profoundly influence the type of response that is elicited under else identical conditions. In mice, gene gun vaccines induce predominantly Th2-biased immune reactions against most antigens. One exception is E. coli beta-galactosidase (βGal) that induces a balanced Th1/Th2 response. Because both, the delivered material (plasmid DNA-coated gold particles) as well as the procedure (biolistic delivery to the skin surface) is the same as for other antigens we hypothesized that Th1 induction could be a function of βGal protein expressed in transfected cells. To test this we examined gene gun vaccines encoding structural or functional variants of the antigen. Employing a series of gene gun vaccines encoding individual structural domains of βGal, we found that neither of them induced IgG2a antibodies. Even disruption of the homo-tetramer association of the native protein by deletion of a few N-terminal amino acids was sufficient to abrogate IgG2a production. However, enzymatically inactive βGal with only one point mutation in the catalytic center retained the ability to induce Th1 reactions. Thus, structural but not functional integrity of the antigen must be retained for Th1 induction. βGal is not a Th1 adjuvant in the classical sense because neither were βGal-transgenic ROSA26 mice particularly Th1-biased nor did co-administration of a βGal-encoding plasmid induce IgG2a against other antigens. Despite this, gene gun vaccines elicited Th1 reactions to antigens fused to the open reading frame of βGal. We interpret these findings as evidence that different skin-borne antigens may be differentially handled by the immune system and that the three-dimensional structure of an antigen is an important determinant for this.
Highlights
For the establishment of protective immunity the type of effector mechanism is a decisive determinant
We found that bGal is an unusual antigen in that it induced multiple IgG isotypes including IgG1, 2a/c and IgG2b. This was even true for BALB/c mice that are genetically biased towards Th2-polarized immunity [42]
We immunized B6 and BALB/c mice with gene gun vaccines encoding different antigens. These included the house dust mite allergen Der p 2, a 129 amino acid (AA) beta-barrel protein with homology to the Tlr4 co-receptor MD-2 [13,43], the cat saliva allergen Fel d 1, a tetramer composed of 2 identical heterodimers of 92 and AA a-helical polypeptides [44], Phl p 6, a AA a-helical Zn-binding polypeptide [45] and hen egg albumin (OVA), a member of the serpin superfamily of 386 AA [46]. pCI-bGal induced comparable amounts of IgG1 and IgG2a whereas with other antigens IgG2a:IgG1 ratios were only low
Summary
For the establishment of protective immunity the type of effector mechanism is a decisive determinant. E.g., cytotoxic T lymphocytes (CTL) may be effective against intracellular infections, Th1 (but not Th2) reactions against leishmaniasis or lepra [1,2,3,4], and different types of immunoglobulins are differentially involved in a diverse set of defense mechanisms such as phagocytosis, mast cell degranulation or complement activation [5,6]. It has been recognized that biochemical parameters such as the stability of protein folds and accessibility to lysosomal proteolysis can influence immunogenicity [14,15]. In view of the serious threats imposed by intracellular pathogens such as viruses, and tumor antigens, it might be of relevance to understand the influence of host cell-derived antigens on immune modulation
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