The central nervous system (CNS), which is made up of the brain and spinal cord, is considered immune privileged due to its isolation behind the blood-brain barrier and lack of conventional lymphatic drainage. However, it has been shown that the CNS is surveyed by and interacts dynamically with the adaptive immune system. White blood cell immune responses, specifically those of cytotoxic CD8 T cells and helper CD4 T cells, directed towards CNS antigens have been documented. Where these events are initiated and what cellular mechanisms are involved remain unknown.
Â We established an experimental mouse model to evaluate the requirements for priming CD8 T cells towards intracranial antigens. This model is unique in that antigen must be captured by the host brainâ€™s antigen presenting cells (i.e. dendritic cells, macrophages, or microglia) and presented to CD8 T cells through a process known as cross-presentation.
We find that even with a damaged blood-brain barrier, initial antigen cross-presentation occurs in lymph nodes and not within the CNS itself. Only once the responding CD8 T cells have encountered cross-presented antigen in the lymph nodes and undergone expansion can they traffic into the CNS. Cross-presentation of intracranial antigen is efficient, and the subsequent priming of CD8 T cells is dependent on CD4 T cell help and the molecule CD40 expressed by host antigen presenting cells. Our findings have important implications for the initiation of T cell immune responses toward CNS antigens.Â