New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance.

It has long been appreciated that MHC alloantigens can be recognized via two pathways; direct and indirect. The relative contributions of these two pathways to transplant rejection are partially understood. In studies of transplantation tolerance it appears that regulatory T cells (Trs) with indirect allospecificity, particularly the CD4+CD25+ population, play a key role and can regulate responder cells with direct allospecificity for the same alloantigens. One of the conundrums that remains is how helper T and Tr cells with indirect allospecificity regulate T cells with direct allospecificity. At face value, this appears to break the rules of linkage that require interacting T cells to make contact with the same antigen-presenting cell. A third, 'semi-direct' pathway involving MHC exchange may help to resolve this conundrum. Insights into how these pathways interact in transplant immunity and tolerance will assist the pursuit of clinical tolerance.

A novel pathway of antigen presentation by dendritic and endothelial cells: Implications for allorecognition and infectious diseases.

Dendritic cells (DCs) are the major antigen presenting cells capable of stimulating T cell responses following either organ transplantation or a viral infection. In the context of allorecognition, T cells can be activated following presentation of alloantigens by donor DCs (direct), as well as by recipient DCs presenting processed donor major histocompatibility complex (MHC) as peptides (indirect). We have recently described another mechanism by which alloreactive T cells are activated. Recipient DCs can acquire donor MHC through cell-to-cell contact and this acquired MHC can stimulate a T cell response (the semidirect pathway). Similarly, during a viral infection, DCs are capable of stimulating T cells directly, as occurs when infected DCs present processed viral antigens, or indirectly by a process known as cross-presentation. Although cross-presentation of exogenous antigen is an important mechanism for controlling infectious diseases, it is possible that peptide:MHC acquisition (the semidirect pathway) may also play a part in immunity against pathogens. In this review, we discuss the possible contributions of the semidirect pathway/MHC transfer in infectious disease.

Infection of mouse bone marrow-derived dendritic cells with recombinant adenovirus vectors leads to presentation of encoded antigen by both MHC class I and class II molecules-potential benefits in vaccine design.

Dendritic cells (DCs) are highly specialised antigen-presenting cells (APCs) that are essential for the initiation and modulation of T cell-mediated immune responses. In order to induce effective CTL responses against most infections and tumours, DCs must prime both CD4(+) and CD8(+) antigen-specific T cells. It is, therefore, important in vaccine design to produce antigen-delivery systems that lead to the simultaneous presentation of multiple histocompatibility complex (MHC) class I- and class II-restricted antigenic peptides by DCs. In this study, the infection of immature mouse bone marrow-derived DCs (BMDCs) with recombinant adenovirus (rAd) vectors led to a marked upregulation of surface costimulatory molecules, IL-12 p40 production and capacity to stimulate both allogeneic and antigen-specific T cells. Furthermore, infection of immature and mature BMDCs with a rAd encoding chicken ovalbumin (OVA) led to presentation of the antigen to TCR-transgenic OVA-specific CD4(+) and CD8(+) T cells. In addition, the activation state of responding CD8(+) T cells was further amplified if they recognised antigen on rAd-transduced BMDCs in the presence of antigen-specific CD4(+) T cells. The results suggest that rAd-encoded OVA protein is secreted by BMDCs, taken up by endocytosis and presented in association with MHC class II molecules for activation of OVA-specific CD4(+) T cells. Consequently, rAd-transduced immature BMDCs become better stimulators of antigen-specific CD4(+) T cells than rAd-infected mature BMDCs. Taken together, these data have important implications for vaccine design, and suggest that infection of immature DCs with rAd encoding MHC class I and class II-restricted T cell epitopes could be an efficient means of inducing effective immune responses.

A novel pathway of alloantigen presentation by dendritic cells.

In the context of transplantation, dendritic cells (DCs) can sensitize alloreactive T cells via two pathways. The direct pathway is initiated by donor DCs presenting intact donor MHC molecules. The indirect pathway results from recipient DCs processing and presenting donor MHC as peptide. This simple dichotomy suggests that T cells with direct and indirect allospecificity cannot cross-regulate each other because distinct APCs are involved. In this study we describe a third, semidirect pathway of MHC alloantigen presentation by DCs that challenges this conclusion. Mouse DCs, when cocultured with allogeneic DCs or endothelial cells, acquired substantial levels of class I and class II MHC:peptide complexes in a temperature- and energy-dependent manner. Most importantly, DCs acquired allogeneic MHC in vivo upon migration to regional lymph nodes. The acquired MHC molecules were detected by Ab staining and induced proliferation of Ag-specific T cells in vitro. These data suggest that recipient DCs, due to acquisition of donor MHC molecules, may link T cells with direct and indirect allospecificity.