The Effect Of Interaction Between BTLA And HVEM Expressed In Mouse Dendritic Cells On T Cell Activation

T lymphocyte activation involves two signals. The first signal is from the binding of TCR to MHC/peptide complex on antigen presenting cell (APC), the interaction of costimulatory molecules expressed on T cells and APCs produced secondary signals. Dendritic cells (DC) are the most potent antigen presenting cell, which play important roles in tumor immunity, anti-infection immunity, autoimmunity and transplantation immunity.The costimulatory molecules are mainly divided into two categories: tumor necrosis factor receptor superfamily (TNFRSF) and immunoglobulin superfamily (IgSF). HVEM is a member of TNFRSF, BTLA belongs to IgSF. Until recently, it was thought that all these IgSF members interacted with members of the B7 family, and that TNFR-family members interact only with TNF-family ligands. Recently, it was found that crosstalk occurs between the immunoglobulin superfamily and the TNFR family of costimulatory molecules. The interaction between BTLA and herpesvirus-entry mediator (HVEM), a costimulatory tumour necrosis factor receptor, is unique in that it is the only receptor-ligand interaction that directly bridges these two families of receptors.Recent studies show that HVEM could be a receptor which transfers a positive immune signal. When HVEM acts as a ligand and interacted with BTLA, it transfers a negative immune signal. BTLA can be phosphorylated after binding to HVEM, and negatively regulate T-cell responses. HVEM-BTLA represents a new pair of coinhibitory molecules.The first part of this work was to investigate the expression changes of the costimulatory molecule HVEM on the mouse bone marrow-derived dendritic cells (BMDC) in the presence of DC mature and activating factors (LPS, TNF-α, 4-1BB agonist antibody 2A, CD40 agonist antibody 1c10) and negative immuno-regulatory factor (IL-10). The results showed that the expression of HVEM on BMDC cultured with DC mature and activating factors were obviously down-regulated in comparison with control group(P<0.05), In contrast, their expressions on BMDC cultured with IL-10 were obviously up-regulated toward control group(P<0.05). These results suggest that LPS, TNF-α, 2A, 1c10 may down-regulate the level of HVEM expression on DC, lower the threshold of T-cell activation when cultured with T cells. In contrast, one of another possible mechanisms about the inhibitory function of IL-10 to DC is to up-regulate the level of HVEM expression on DC. Therefore, the threshold of T-cell activation was enhanced, leading to weak T cell responses.The second part studied the influence of blocking DC by anti-HVEM antibodies on the activation of T cells (especially early activation) and on the secretion of IL-2. Our study revealed that, both in the early period (0-48h) and later period (48-96h) of the MLR, stronger T cell proliferation could be observed in anti-HVEM antibody groups in comparison to controls. So was the secretion of IL-2. Notably, BTLA had a inhibitory effect on T-cell activation in the early period (0-48h). This phenomenom is paradoxical with the already known feedback negative regulation theory for T cells, suggesting there are more than one ways to regulate T cell activation.In conclusion, this work revealed LPS, TNF-α, 2A, 1c10 can down-regulate the level of HVEM expression on DC, IL-10 can up-regulate the level of HVEM expression on DC. Both in the early period (0-48h) and later period (48-96h) of the MLR, especially the early period, stronger T cell proliferation could be observed, suggesting there are more than one ways to regulate T cell responses.