Abstract
CD1d is an MHC class I-like molecule comprised of a transmembrane glycoprotein (heavy chain) associated with β2-microglobulin (β2m) that presents lipid antigens to NKT cells. Initial folding of the heavy chain involves its glycan-dependent association with calreticulin (CRT), calnexin (CNX), and the thiol oxidoreductase ERp57, and is followed by assembly with β2m to form the heterodimer. Here we show that in CRT-deficient cells CD1d heavy chains convert to β2m-associated dimers at an accelerated rate, indicating faster folding of the heavy chain, while the rate of intracellular transport after assembly is unaffected. Unlike the situation with MHC class I molecules, antigen presentation by CD1d is not impaired in the absence of CRT. Instead, there are elevated levels of stable and functional CD1d on the surface of CRT-deficient cells. Association of the heavy chains with the ER chaperones Grp94 and Bip is observed in the absence of CRT, and these may replace CRT in mediating CD1d folding and assembly. ER retention of free CD1d heavy chains is impaired in CRT-deficient cells, allowing their escape and subsequent expression on the plasma membrane. However, these free heavy chains are rapidly internalized and degraded in lysosomes, indicating that β2m association is required for the exceptional resistance of CD1d to lysosomal degradation that is normally observed.
Highlights
CD1 molecules are encoded by a family of linked genes located outside the major histocompatibility complex (MHC)2
Similar to the way that MHC class I- and class II-restricted T cells can recognize peptide antigens presented by MHC glycoproteins, lipid antigens associated with CD1 molecules can be recognized by effector T cells [5, 6]
Once released from the CNX/CRT cycle, fully oxidized CD1d heavy chains associate with 2m and enter the Golgi where the glycans are further processed before transport to the plasma membrane
Summary
CD1 molecules are encoded by a family of linked genes located outside the major histocompatibility complex (MHC)2 (reviewed in Ref. 1). Significant expression of free CD1d heavy chains was detected on the surface of the CRT-deficient cells (Fig. 6A).
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