Proteasomes, TAP and ERAAP control CD4+ Th cell responses by regulating indirect presentation of MHC class II-restricted cytoplasmic antigens

Abstract

Cytoplasmic antigens derived from viruses, cytosolic bacteria, tumours and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted antigens, professional antigen-presenting cells 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, or class I-processing machinery—which supplies peptides for presentation by class I molecules—plays very little role in indirect presentation of class II-restricted, cytoplasmic antigens. Remarkably, upon testing this assumption, proteasomes, TAP and ERAAP, but not tapasin, partially destroyed or removed cytoplasmic, class II-restricted antigens such that their inhibition or deficiency led to dramatically increased Th cell responses to cytosolic allograft (HY) and microbial (Listeria monocytogenes) antigens, and uncovered novel class II-restricted self-epitopes and those derived from SV40 large T antigen. From these findings, and the altered repertoire of class II-restricted self-peptides presented by wild type, TAP- and ERAAP-deficient cells, a novel model emerges in which the class I-processing machinery regulates the quantity, as well as quality of cytoplasmic peptides available for presentation by class II molecules, and hence modulates TH cell responses, as well as Th T cell receptor repertoire.