MHC-II peptidome of the CNS reveals endogenous guardian peptides

The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect it, is not entirely isolated from the immune system. In fact, it remains physically connected to and can be influenced by the peripheral immune system. How the CNS retains such responsiveness while maintaining “immune privilege” remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered a repertoire of CNS-derived endogenous guardian peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, a preponderance of these guardian peptides were found to be bound to MHC II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. With neuroinflammatory disease, however, the presentation of guardian peptides was diminished. Fascinatingly, boosting the presence of these guardian peptides reinforced a population of suppressor CD4+ T cells and significantly reduced CNS autoimmune disease. This unexpected discovery of CNS-derived autoimmune guardian peptides may be the molecular key adapting the CNS to receive information and to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases. Mice were immunized with MOG(35-55) or MOG(35-55) and MBP(160-175) and then 10 days after immunization cells from the draining (inguinal) lymph nodes were harvested. Cells were sorted based on DAPI (live cells) as well as Thy1.2 and TCRb to get T cells from which we get both CD4 and CD8. 3 male C57BL/6J mice were used for each group.