In the absence of the invariant chain, HLA-DR molecules display a distinct array of peptides which is influenced by the presence or absence of HLA-DM

Abstract

The independent inf luences of invariant chain (Ii) and HLA-DM molecules on the array of naturally processed peptides displayed by HLA-DR molecules were studied using transfected cell lines. Major histocompatibility complex (MHC) class II molecules present peptide antigens to MHC class II-restricted CD4 ϩ T cells. The peptides presented are usually derived from internalized exogenous or membrane-bound proteins (1) which are unfolded, denatured, and degraded within the progressively acidic endosomal pathway. Class II molecules are assembled in the endoplasmic reticulum (ER), where they associate noncovalently with the invariant chain (Ii), a type 2 transmembrane protein (reviewed in ref.2). The CLIP region of Ii (amino acids 81-104) binds in the groove of nascent MHC class II molecules, thereby inhibiting the binding of peptides in the ER (3-5). An endosomal targeting motif within the amino terminus of the p33 form of Ii directs the Ii-class II complexes to specialized endosomal compartments, MIIC (6, 7). Here, Ii is sequentially degraded by proteases, and the catalytic activity of HLA-DM promotes exchange of CLIP for peptides derived from endocytosed proteins (8-11).In the absence of Ii, as shown in Ii knockout mice (Ii 0/0 ), few class II molecules reach the cell surface, as most are retained in the ER and degraded (12, 13). The studies of antigen presentation by Ii-negative (Ii Ϫ ) cells reported to date have largely used T cell clones or hybridomas raised against conventional antigen-presenting cells (APC) as responders. The results of such studies have shown that a degree of overlap exists between the peptides displayed by MHC class II molecules expressed in the presence and the absence of Ii (for example, see ref. 14). However, this approach does not inform whether the complete or relative absence of Ii leads to the display of novel peptide epitopes by MHC class II molecules, an important issue if circumstances can arise in vivo in which Ii is limiting in MHC class II ϩ cells.In this study we used alloreactive T cell clones as probes of peptide occupancy of class II molecules expressed in the presence or absence of Ii and HLA-DM on the basis that anti-MHC allorecognition generally involves the corecognition of the allogeneic MHC molecule and bound peptide (for review see ref. 15). The results suggest that in the absence of Ii, MHC class II molecules display a distinct array of peptides. Furthermore, HLA-DM influenced allorecognition of DR molecules in the absence of Ii, suggesting that HLA-DM can influence MHC class II peptide occupancy independently of Ii. Taken together, these findings support the prediction that discordant regulation of MHC class II, Ii, and HLA-DM molecules in vivo, as has been observed in bone marrow macrophages (16) and in gut epithelial cells (17) for MHC and Ii, could lead to the display of self-peptides to which the T cell repertoire is not tolerant.

Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands

“…The influence of this expression in in vivo autoimmune responses is not clear, but some autoepitopes are uniquely processed and presented by the endocrine cells to CD4 ϩ T cells, what may explain their specific destruction. The relative levels of expression of Ii and DM are maintained in professional APCs (18,31), whereas class II ϩ epithelial cells show variable levels of MHC II, Ii, and DM, particularly in the context of autoimmunity and tumor immunity (7,21,22). These variations are expected to influence the repertoire of peptides presented by the epithelial cells.…”

HLA-DMB expression by thyrocytes: indication of the antigen-processing and possible presenting capability of thyroid cells

“…In H2-M (the mouse equivalent of DM)-deficient mice, normal amounts of class II molecules are present on the cell surface, but most of them are associated with CLIP peptides; the CD4 þ T cells from the deficient mice failed to respond to self-antigen-presenting cells (APC), but reacted strongly to wild-type APC [8]. Discordant regulation of HLA-DM, invariant chain (Ii) and class II molecules may enable HLA class II molecules to present novel self-peptides to which the T cells are not tolerant [9]. Although a number of studies have been done on MHC class II expression in autoimmune diseases [10], to our knowledge no work has been published on HLA-DM expression on the autoimmune target cells.…”

Interaction of Human Immunodeficiency Virus Type 2 Vpx and Invariant Chain

“…1) (25,28). In the absence of the Ii chaperone, ␣ and ␤ chains of MHC class II accumulate in the endoplasmic reticulum (ER) and demonstrate increased binding activity for endogenous peptides (7,27,34).…”