Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins

John D. Lich, John F. Elliott, Janice Blum

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Biochemical and functional studies have demonstrated major histocompatibility complex (MHC) class II-restricted presentation of select epitopes derived from cytoplasmic antigens, with few insights into the processing reactions necessary for this alternate pathway. Efficient presentation of an immunodominant epitope derived from glutamate decarboxylase (GAD) was observed regardless of whether this antigen was delivered exogenously or via a cytoplasmic route into human histocompatibility leukocyte antigen class II-DR4+ antigen-presenting cells. Presentation of exogenous as well as cytoplasmic GAD required the intersection of GAD peptides and newly synthesized class II proteins. By contrast, proteolytic processing of this antigen was highly dependent upon the route of antigen delivery. Exogenous GAD followed the classical pathway for antigen processing, with an absolute requirement for endosomal/lysosomal acidification as well as cysteine and aspartyl proteases resident within these organelles. Presentation of endogenous GAD was dependent upon the action of cytoplasmic proteases, including the proteasome and calpain. Thus, translocation of processed antigen from the cytoplasm into membrane organelles is necessary for class II-restricted presentation via this alternate pathway. Further trimming of these peptides after translocation was mediated by acidic proteases within endosomes/lysosomes, possibly after or before class II antigen binding. These studies suggest that processing of exogenous and cytoplasmic proteins occurs through divergent but overlapping pathways. Furthermore, two cytoplasmic proteases, the proteasome and calpain, appear to play important roles in MHC class II-restricted antigen presentation.

Original languageEnglish
Pages (from-to)1513-1523
Number of pages11
JournalJournal of Experimental Medicine
Volume191
Issue number9
DOIs
StatePublished - May 1 2000

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Glutamate Decarboxylase
Antigen Presentation
Major Histocompatibility Complex
Histocompatibility Antigens Class II
Antigens
Peptide Hydrolases
Calpain
Proteasome Endopeptidase Complex
Proteins
Organelles
Aspartic Acid Proteases
Immunodominant Epitopes
Peptides
Cysteine Proteases
Endosomes
Antigen-Presenting Cells
HLA Antigens
Lysosomes
Epitopes
Cytoplasm

Keywords

  • Calpain
  • Cathepsin
  • Cytoplasm
  • Protease
  • Proteasome

ASJC Scopus subject areas

  • Immunology

Cite this

Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. / Lich, John D.; Elliott, John F.; Blum, Janice.

In: Journal of Experimental Medicine, Vol. 191, No. 9, 01.05.2000, p. 1513-1523.

Research output: Contribution to journalArticle

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