Modulation of the Major Histocompatibility Complex Class II-associated Peptide Repertoire by Human Histocompatibility Leukocyte Antigen (HLA)-DO

doi:10.1084/jem.191.7.1127

Published online 27 March 2000.

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© The Rockefeller University Press, 0022-1007/2000/4/1127/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 7, April 3, 2000 1127-1136

Original Article

Modulation of the Major Histocompatibility Complex Class II–associated Peptide Repertoire by Human Histocompatibility Leukocyte Antigen (HLA)-DO

Marieke van Ham^a, Marcel van Lith^a, Björn Lillemeier^c, Esther Tjin^a, Ulrike Grüneberg^e, Dinah Rahman^d, Liesbeth Pastoors^b, Krista van Meijgaarden^f, Corinne Roucard^g, John Trowsdale^e, Tom Ottenhoff^f, Darryl Pappin^d, and Jacques Neefjes^a
^a Division of Tumor Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
^b Division of Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
^c Biochemical Regulatory Mechanisms Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom
^d Protein Sequencing Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom
^e Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom
^f Department of Immunohaematology and Bloodbank, Leiden University Medical Center, 2333 2A Leiden, The Netherlands
^g Groupe de Recherche sur les Lymphomes, Institut Albert Bonniot, 38706 La Tronche, France

Correspondence to: Marieke van Ham, Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel:31-20-512-2023 Fax:31-20-512-2029 E-mail:vanham{at}nki.nl.

Antigen presentation by major histocompatibility complex classII molecules is essential for antibody production and T cellactivation. For most class II alleles, peptide binding dependson the catalytic action of human histocompatibility leukocyteantigens (HLA)-DM. HLA-DO is selectively expressed in B cellsand impedes the activity of DM, yet its physiological role remainsunclear. Cell surface iodination assays and mass spectrometryof major histocompatibility complex class II–eluted peptidesshow that DO affects the antigenic peptide repertoire of classII. DO generates both quantitative and qualitative differences,and inhibits presentation of large-sized peptides. DO functionwas investigated under various pH conditions in in vitro peptideexchange assays and in antigen presentation assays using DO^-and DO⁺ transfectant cell lines as antigen-presenting cells,in which effective acidification of the endocytic pathway wasprevented with bafilomycin A₁, an inhibitor of vacuolar ATPases.DO effectively inhibits antigen presentation of peptides thatare loaded onto class II in endosomal compartments that arenot very acidic. Thus, DO appears to be a unique, cell type–specificmodulator mastering the class II–mediated immune responseinduced by B cells. DO may serve to increase the threshold fornonspecific B cell activation, restricting class II–peptidebinding to late endosomal compartments, thereby affecting thepeptide repertoire.

Key Words: antigen presentation, immune response, selection, HLA-DM, autoimmunity

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