The blood–brain barrier was once thought to prevent the peripheral immune system interacting with the central nervous system (CNS), to limit autoimmunity. However, a lymphatic system exists at the borders where CNS antigens can be presented to circulating immune cells, so the question arises as to how immune tolerance to the structures of the brain is maintained. A mass spectrometry-based MHC II peptidomic screen of mouse CNS now published in Nature shows that the presentation of regulatory self-peptides can protect against autoreactivity by promoting immunosuppressive Tr1-like CD4+ T cells during homeostasis. The authors show that immunization of mice with specific myelin basic protein (MBP) peptides does not cause pathology or T cell reactivity as occurs with immunization of myelin oligodendrocyte glycoprotein (MOG). In fact, immunization of mice with MBP160–175 peptides even protected against neuroinflammation. Using a tetramer system to tag T cells specific for these peptides, they show an immunosuppressive T cell repertoire in the draining lymph nodes, with an abundance of MBP160–175-specific FOXP3− T cells that produce the regulatory molecules TGFβ and CTLA-4. The authors also screened EAE mice and saw a peptidome shift away from these protective peptides and the antigen-presenting cells that present them. Injection of extracellular vesicles containing MBP160–175 into the cerebrospinal fluid of EAE mice, resulted in expansion of the immunosuppressive T cell population and reduced pathology.

Original reference: Nature https://doi.org/10.1038/s41586-024-08279-y (2024)