Human Dendritic Cells Are Superior to B Cells at Presenting a Major Histocompatibility Complex Class II-Restricted Heterologous Antigen Expressed on RecombinantStreptococcus gordonii

Abstract

Bacteria are being actively investigated as vaccine carriers for inducing or boosting protective immune responses. In this study, human monocyte-derived dendritic cells (DCs) and normal B cells were compared for their capacity to present the C fragment of tetanus toxin (TTFC), expressed on the surface of recombinant Streptococcus gordonii, to specific CD4 ؉ T lymphocytes. DCs were more efficient than B cells at presenting soluble TTFC and remarkably more capable of presenting bacterium-associated TTFC both in terms of the amount of antigen required to obtain a given T-cell response and on a per-cell basis. This difference was associated with a much lower capacity of B cells to endocytose soluble TTFC and phagocytose recombinant S. Recent efforts in developing more efficacious vaccine strategies have pointed to the use of bacteria as vectors of heterologous antigens. Bacteria can be easily manipulated at the genetic level and can be engineered to express the gene product in different forms (11,21,26). Alternatively, attenuated bacteria can serve as carriers for delivering antigen-encoding DNA to antigen-presenting cells (APCs) (6,17,30). These approaches have been used for inducing protective immune responses against viral and tumor antigens in mouse models (6,17,26). In particular, recombinant strains of Streptococcus gordonii, which is a commensal bacterium of the human oral cavity, induce both local and systemic antibody responses, as well as a T-cell response, to viral antigens in both mice and macaques (7,15,16). However, the APCs and the mechanisms involved in these bacterium-based immunostimulating systems have been only marginally investigated.Dendritic cells (DCs) and B lymphocytes show important differences in their APC functions (1, 19). They differ in the capacity to endocytose antigens, to cluster with T cells, to provide proper costimulation, and to secrete regulatory cytokines (2,5,9,13,28). A number of studies have indeed demonstrated that DCs are much more potent APCs than are antigen-specific and non-antigen-specific B lymphocytes in the activation of both naive and memory T cells (2,4,9,14,20,27). Most experiments, however, has been performed using soluble antigens given in the form of native proteins or immunogenic peptides, and very few studies have compared the capacity of DCs and B cells to present particulate or bacterium-associated antigens (8,23,29).Mouse DCs present a major histocompatibility complex (MHC) class I-restricted heterologous antigen, expressed on the surface of recombinant S. gordonii, to T lymphocytes at high efficiency, and S. gordonii induces neobiosynthesis and membrane stabilization of MHC class I and class II molecules (25). Moreover, human DCs fed with recombinant bacteria stimulated the specific CD4 ϩ -T-cell response with much higher efficiency than did DCs pulsed with soluble antigen. Finally, S. gordonii provided a potent stimulus for inducing DC maturation and release of chemokines active on T cells (3). In the present study, DCs and B cells were compared for th...

Stimulation of Human Monocytes with the Gram-Positive Vaccine VectorStreptococcus gordonii

“…In conclusion, this work shows that the immunostimulatory activity of the vaccine vector S. gordonii is not restricted to the induction of DC maturation (3,4,30) but also affects the differentiation process of human monocytes. …”

“…The model antigens expressed on the surfaces of recombinant bacteria are processed and presented by DCs not only in association with major histocompatibility complex (MHC) class II but also MHC class I molecules much more efficiently than the soluble antigen (30). Furthermore, human DCs were more efficient than B cells at presenting the heterologous antigen expressed on the surface of S. gordonii (4).…”

“…We have previously demonstrated that S. gordonii is efficiently internalized by both murine and human dendritic cells (DCs), and it induces their maturation and activation as shown by phenotypic and functional changes (3,4,30). The model antigens expressed on the surfaces of recombinant bacteria are processed and presented by DCs not only in association with major histocompatibility complex (MHC) class II but also MHC class I molecules much more efficiently than the soluble antigen (30).…”

In Vivo Activation of Naive CD4+T Cells in Nasal Mucosa-Associated Lymphoid Tissue following Intranasal Immunization with RecombinantStreptococcus gordonii

“…Single-cell suspensions from NALT, cervical lymph nodes, and spleens were incubated with an Fc-blocking solution (0. 5 …”

“…A variety of antigens, of different origins and sizes, have been expressed on the surface of S. gordonii (25,30) and were shown to be immunogenic by the systemic and mucosal routes (oral, vaginal, and intragastric) in both mice and monkeys (6, 22-24, 26, 29, 31, 41). S. gordonii is efficiently internalized by both human and mouse dendritic cells (DCs), inducing their maturation and activation (4,5,39), and the heterologous antigen is presented by DCs in association with not only major histocompatibility complex (MHC) class II but also MHC class I molecules (39). Most importantly, it has recently been shown in a phase I clinical trial that S. gordonii is safe in humans when administered by the nasal/oral route and that it can be rapidly eradicated either spontaneously or with antibiotic treatment (14).…”