The Journal of Experimental Medicine
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Published online 13 March 2000.
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© The Rockefeller University Press, 0022-1007/2000/3/927/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 6, March 20, 2000 927-936

Original Article

The Formation of Immunogenic Major Histocompatibility Complex Class II–Peptide Ligands in Lysosomal Compartments of Dendritic Cells Is Regulated by Inflammatory Stimuli

Kayo Inabaa, Shannon Turleyb, Tomonori Iyodaa, Fumiya Yamaidea, Susumu Shimoyamaa, Caetano Reis e Sousac, Ronald N. Germainc, Ira Mellmanb, and Ralph M. Steinmand
a Laboratory of Immunobiology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan
b Department of Cell Biology, Yale University Medical School, New Haven, Connecticut 06520-8002
c Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892
d Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York 10021-6399

Correspondence to: Ralph M. Steinman, Laboratory of Cell Physiology and Immunology, The Rockefeller University, 405 Bronk Bldg., 1230 York Ave., New York, NY 10021-6399. Tel:212-327-8106 Fax:212-327-8875 E-mail:steinma{at}rockvax.rockefeller.edu.

Released online: 13 March 2000

During their final differentiation or maturation, dendritic cells (DCs) redistribute their major histocompatibility complex (MHC) class II products from intracellular compartments to the plasma membrane. Using cells arrested in the immature state, we now find that DCs also regulate the initial intracellular formation of immunogenic MHC class II–peptide complexes. Immature DCs internalize the protein antigen, hen egg lysozyme (HEL), into late endosomes and lysosomes rich in MHC class II molecules. There, despite extensive colocalization of HEL protein and MHC class II products, MHC class II–peptide complexes do not form unless the DCs are exposed to inflammatory mediators such as tumor necrosis factor {alpha}, CD40 ligand, or lipoplolysaccharide. The control of T cell receptor (TCR) ligand formation was observed using the C4H3 monoclonal antibody to detect MHC class II–HEL peptide complexes by flow cytometry and confocal microscopy, and with HEL-specific 3A9 transgenic T cells to detect downregulation of the TCR upon MHC–peptide encounter. Even the binding of preprocessed HEL peptide to MHC class II is blocked in immature DCs, including the formation of C4H3 epitope in MHC class II compartments, suggesting an arrest to antigen presentation at the peptide-loading step, rather than an enhanced degradation of MHC class II–peptide complexes at the cell surface, as described in previous work. Therefore, the capacity of late endosomes and lysosomes to produce MHC class II–peptide complexes can be strictly controlled during DC differentiation, helping to coordinate antigen acquisition and inflammatory stimuli with formation of TCR ligands. The increased ability of maturing DCs to load MHC class II molecules with antigenic cargo contributes to the >100-fold enhancement of the subsequent primary immune response observed when immature and mature DCs are compared as immune adjuvants in culture and in mice.

Key Words: dendritic cell, maturation, MHC class II–peptide complex, lysosome, inflammation


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