Recent advances in mass spectrometry technology have facilitated detailed examination of MHC-II immunopeptidomes, for example the repertoires of peptides bound to MHC-II molecules expressed in antigen presenting cells. These studies have deepened our view of MHC-II presentation. Other studies have broadened our view of pathways leading up to peptide loading. Here we review these recent studies in the context of earlier work on conventional and non-conventional MHC-II processing. The message that emerges is that sources of antigen beyond conventional endosomal processing of endocytosed proteins are important for generation of cellular immune responses to pathogens and maintenance of central and peripheral tolerance. The multiplicity of pathways results in a broad MHC II immunopeptidome that conveys the sampled environment to patrolling T cells.
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