Reporting in Nature, Kipnis and colleagues show that endogenous self-peptides derived from central nervous system (CNS) antigens are presented on MHC class II (MHCII) molecules at the borders of the CNS and can act as ‘guardians’ of immune privilege by expanding suppressive populations of CD4+ T cells.

To explore how immune tolerance is maintained to CNS antigens, the authors characterized the MHCII peptidome in the mouse CNS and its associated borders. They identified CD11b+CD11c− macrophages as the predominant MHCII+ antigen-presenting cells (APCs) in the brain and dura, and B cells as the main MHCII+ APCs in the deep cervical and superficial cervical lymph nodes (DCLNs and SCLNs, respectively). They showed heterogeneity in the repertoire of peptides presented on MHCII molecules in these different compartments, with CNS-derived peptide presentation enriched in the brain leptomeninges and dura, compared with the DCLNs and SCLNs. With currently available prediction algorithms, peptide-binding affinities were also noted to be weaker in the brain and dura compared with the draining lymph nodes. Further analyses showed many peptides derived from myelin basic protein (MBP), an abundant protein in the CNS, are presented in the brain, dura and DCLNs, but not the SCLNs.