Efficient Dendritic Cell Maturation and Initiation a Strong T Cell Immune Response Requires B7-H1-Mediated Dendritic Cell ‘Conditioning’ During Interaction with T Cells

One of the prominent features of the adaptive immune system is the extensive interactions between T cells and dendritic cells (DCs). The T cell-DC interactions are essential for T cell development, homeostasis, and activation, and require two signals, known as ‘The two signal model’. The first signal is initiated by T cell receptor (TCR) upon recognition of antigen in the form of peptides presented by the major histocompatibility complex (MHC) molecules. The second signal is mediated by engagement of co-regulatory molecules on naive T cells with its counterpart expressed by mature DCs. Depending on the nature of the regulatory signal both, DCs and T cells are affected. In this PhD work, we demonstrate the dual characteristics of the co-regulatory B7-H1 (PD-L1) molecules. B7-H1 expression in peripheral tissues such as the lung, during the peak of infection, negatively influenced antigen-specific T cell response and induced T cell apoptosis, most likely by binding to the inhibitory PD-1 receptor on T cells. This result suggests that inhibitory B7-H1:PD-1 interaction provides a mechanism to limit the excessive accumulation of effector T cells in the lung after the virus is cleared. More importantly, this study shows a novel stimulatory function of the B7-H1 molecules that are expressed on T cells in regulation of DC development and maturation. Flow cytometric analysis revealed that following WSN-SIY influenza infection, dendritic cell maturation in B7-H1-/- mice is defective and consequently CD8 T cell response is diminished. The adoptive transfer of B7-H1-expressing T cells however completely restored DC maturation in the draining lymphnode and enhanced CD8 T cell response, such as activation and proliferation. Moreover, maturation-defective DCs in T and B cell-deficient RAG-1 knock-out mice after influenza infection were also rescued by B7-H1+ T cells. Further analyses demonstrated the rescue of T cell response in B7-H1-/- mice by transfer of immature DCs from either B7-H1+/+ wild type mice or RAG-1-/- mice that had previously received B7-H1+ T cells. These findings illustrate the molecular requirement for T cell-dependent DC maturation and describe the cellular interactions that promote efficient T cell responses to microbial infection. It is essential that DCs acquire a B7-H1-mediated conditioned state during interaction with T cells before efficient DC maturation upon antigen-stimulation is enabled.