Immune surveillance for ERAAP dysfunction

Abstract

The ER aminopeptidase associated with antigen processing, ERAAP (or ERAP1), is essential for trimming peptides that are presented by MHC class I molecules. ERAP1 is inhibited by human cytomegalovirus, and ERAP1 polymorphisms are associated with autoimmune diseases. How the immune system detects ERAAP dysfunction, however, is unknown. We have shown previously that ERAAP-deficient cells present an immunogenic pMHC I repertoire, that elicits CD8+ T cell response in WT mice. Additionally, we discovered that the WT CD8+ T cells recognized novel peptides presented by non-classical, or MHC class Ib, molecules on ERAAP-deficient cells. The MHC Ib restricted WT CD8 T cells eliminated ERAAP-deficient cells in vitro and in vivo. We identified the FL9 peptide, presented by Qa-1(b), a MHC class Ib molecule exclusively on ERAAP-deficient cells. Remarkably, T cells specific for the FL9-Qa-1(b) complex were frequent in naïve WT mice, and had an antigen-experienced phenotype. Thus, novel non-classical pQa-1(b) complexes direct cytotoxic T cells to target cells with defective peptide processing in the endoplasmic reticulum. Here, we discuss the implications of our findings, and the possible roles of pMHC Ib-specific T cells in immune surveillance for ERAAP dysfunction.

Figure 1

Immune surveillance for ERAAP dysfunction Peptide trimming is impaired in cells that lack ERAAP. Altered peptide-MHC I complexes are exported to the surface of these cells, forming an immunogenic pMHC I repertoire. WT CD8 T cells detect novel pMHC I complexes on ERAAP-deficient cells, presented by both classical MHC class Ia, and non-classical MHC class Ib, molecules. WT mice naturally have a large number of T cells, called QFL T cells, specific to the Qa-1-FL9 complex, expressed only on ERAAP-deficient cells. QFL T cells, and other pMHC I-specific T cells participate in immune surveillance for ERAAP dysfunction.