Weak base amines can inhibit class I MHC-restricted antigen presentation.
This report describes the effects of NH4Cl, CH3NH2, and chloroquine on class I and II MHC-restricted Ag presentation. OVA-specific T-T hybridomas were used to detect processed OVA in association with class I, H-2Kb, and class II, I-Ad/b, molecules on a B lymphoblastoid APC. OVA, internalized by APC under hypertonic conditions, was presented in association with class I and II MHC molecules. Treating the APC with NH4Cl or CH3NH2 inhibited class I- and II-restricted Ag presentation. In contrast, chloroquine markedly inhibited class II, but not class I-restricted Ag presentation. Controls indicated that drug-treated APC were fully competent to interact with T cells and present processing-independent antigenic peptides in association with both class I and II MHC molecules. NH4Cl and CH3NH2 did not inhibit the uptake of radiolabeled Ag by the APC. After the proteolytic removal of H-2Kb from the surface of APC, NH4Cl and CH3NH2-treated and control APC regenerated identical amounts of surface H-2Kb and this regeneration required de novo protein synthesis. These latter results indicate that NH4Cl and CH3NH2 can inhibit Ag presentation without affecting the synthesis, transport, or surface expression of H-2Kb. Also, NH4Cl did not affect the transport of H-2Db to the surface of mutant RMA-S cells that were cultured with exogenous peptides. Taken together these results strongly suggest that NH4Cl and CH3NH2 but not chloroquine can inhibit a critical and early intracellular step in class I-restricted Ag presentation while simultaneously inhibiting class II-restricted Ag presentation.
Michalek
M T
MT
Department of Pathology, Harvard Medical School, Boston, MA 02115.
Benacerraf
B
B
Rock
K L
KL
D000588:Amines / Q000494:pharmacology*; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006825:Hybridomas; D007376:Interleukin-2 / Q000096:biosynthesis; D008247:Lysosomes / Q000187:drug effects; D008744:Methylamines / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D014176:Protein Biosynthesis / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology
D000588:Amines; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D008744:Methylamines; D000643:Ammonium Chloride; D002738:Chloroquine; D010047:Ovalbumin; C027451:methylamine