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Cytoplasmic Ags derived from viruses, cytosolic bacteria, tumors, and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professional APCs acquire them during uptake of dead class II-negative cells and present them via a process called indirect presentation. It is generally assumed that the cytosolic Ag-processing machinery, which supplies peptides for presentation by class I molecules, plays very little role in indirect presentation of class II-restricted cytoplasmic Ags. Remarkably, upon testing this assumption, we found that proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with Ag processing, but not tapasin, partially destroyed or removed cytoplasmic class II-restricted Ags, such that their inhibition or deficiency led to dramatically increased Th cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags, both of which are indirectly presented. This effect was neither due to enhanced endoplasmic reticulum-associated degradation nor competition for Ag between class I and class II molecules. From these findings, a novel model emerged in which the cytosolic Ag-processing machinery regulates the quantity of cytoplasmic peptides available for presentation by class II molecules and, hence, modulates Th cell responses.

Original publication

DOI

10.4049/jimmunol.1100525

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

06/2011

Volume

186

Pages

6683 - 6692

Addresses

Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2363, USA.

Keywords

T-Lymphocytes, Helper-Inducer, Cytoplasm, Endoplasmic Reticulum, Listeria monocytogenes, Proteasome Endopeptidase Complex, Aminopeptidases, ATP-Binding Cassette Transporters, Antigens, Bacterial, Histocompatibility Antigens Class II, Transplantation, Homologous, Antigen Presentation