Origin and Processing of MHC Class II Ligands

TY - CHAP

T1 - Origin and Processing of MHC Class II Ligands

AU - Watts, Colin

AU - Manoury, Bénédicte

N1 - Publisher Copyright: © 2026 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

PY - 2025/10/30

Y1 - 2025/10/30

N2 - Unlike class I MHC that assembles with peptide in the ER, Class II MHC (MHC-II) engages peptides in endosomes and lysosomes. MHC-II therefore provides a readout of proteins that enter that pathway, whether they be from endocytosed pathogens and/or their products, or self-proteins that have gained access to the pathway. MHC-II-associated peptides have no formal constraint on their length (unlike those on class I MHC-associated peptide, normally 8-10 residues) because the binding groove is open ended. Two dedicated chaperones are necessary for MHC-II molecules to operate effectively. First, newly translated and ER-translocated MHC-II alpha and beta chains assemble with a type II membrane protein called Invariant chain (Ii). Ii acts as both a guardian of the peptide binding site during the early stages of MHC-II biosynthesis and as a targeting sub-unit, which ensures delivery of class II to the endo-lysosome system. Here, Ii is removed by a combination of proteolysis and the action of a second key chaperone DM which as outlined below catalyses replacement of a residual invariant chain peptide (CLIP) with an antigenic or self-peptide. Peptides generated in lysosomes by a different set of proteases are loaded on MHC-II molecules and travel to the cell surface where they have an extended lifetime. Together the combination of chaperones and proteases influence which peptides are presented on MHC-II for immunosurveillance.

AB - Unlike class I MHC that assembles with peptide in the ER, Class II MHC (MHC-II) engages peptides in endosomes and lysosomes. MHC-II therefore provides a readout of proteins that enter that pathway, whether they be from endocytosed pathogens and/or their products, or self-proteins that have gained access to the pathway. MHC-II-associated peptides have no formal constraint on their length (unlike those on class I MHC-associated peptide, normally 8-10 residues) because the binding groove is open ended. Two dedicated chaperones are necessary for MHC-II molecules to operate effectively. First, newly translated and ER-translocated MHC-II alpha and beta chains assemble with a type II membrane protein called Invariant chain (Ii). Ii acts as both a guardian of the peptide binding site during the early stages of MHC-II biosynthesis and as a targeting sub-unit, which ensures delivery of class II to the endo-lysosome system. Here, Ii is removed by a combination of proteolysis and the action of a second key chaperone DM which as outlined below catalyses replacement of a residual invariant chain peptide (CLIP) with an antigenic or self-peptide. Peptides generated in lysosomes by a different set of proteases are loaded on MHC-II molecules and travel to the cell surface where they have an extended lifetime. Together the combination of chaperones and proteases influence which peptides are presented on MHC-II for immunosurveillance.

KW - AEP

KW - Antigen presentation

KW - Antigen processing

KW - Cathepsins

KW - Dendritic cells

KW - DM

KW - DO

KW - GILT

KW - Ii

KW - Lysosomes

KW - Major histocompatibility complex

KW - MHC II

KW - NADPH oxidase

KW - TFEB

KW - Ubiquitination

UR - https://www.sciencedirect.com/referencework/9780128244807/encyclopedia-of-immunobiology

UR - https://www.scopus.com/pages/publications/105028849132

U2 - 10.1016/B978-0-12-824465-4.00216-7

DO - 10.1016/B978-0-12-824465-4.00216-7

M3 - Chapter

AN - SCOPUS:105028849132

SN - 9780128244654

VL - 2

SP - 399

EP - 405

BT - Encyclopedia of Immunobiology

A2 - Kaye, Paul M.

PB - Elsevier

ER -