Microsomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by group 1 CD1 molecules

Background: Lipid antigens are presented to T cells by the non-polymorphic MHC class I-related CD1 molecules and play an important role in a variety of diseases. This laboratory recently reported that microsomal triglyceride transfer protein (MTP), which has until then been known for lipidating apolipoproteins B48 and B100 and generating chylomicrons and VLDL particles, regulates CD1d function and hence natural killer T (NKT) cell biology. While CD1d is expressed in humans and rodents, the type I CD1 genes CD1a, CD1b, and CD1c are only present in humans but not rodents and therefore not accessible for study in murine in vivo disease models.

Aim: We therefore asked whether MTP regulates class I CD1 (CD1a, CD1b, CD1c) antigen presentation, which primarily present microbial lipid antigens, in particular mycobacterial lipid antigens and are key restriction elements for the host immune response.

Methods & Results: Here we report that MTP regulates the function of type 1 CD1 molecules CD1a, CD1b, and CD1c. Pharmacological inhibition of MTP in human monocyte-derived dendritic cells (DC) and the lymphoblastoid B cell line C1R transfected with type 1 CD1 molecules resulted in a substantial decrease in endogenous antigen presenting function to several CD1-restricted T cell lines. Silencing MTP expression in CD1c-transfected Hela cells similarly resulted in decreased antigen presentation. Inhibition of endoplasmic reticulum (ER)-resident MTP decreased presentation of exogenous mycobacterial lipid antigens to CD1a- and CD1c-restricted T cells. Impaired presentation by MTP inhibition was associated with decreased cell surface staining for type 1 CD1 molecules on DCs, but not C1R transfectants. The stability of CD1c heavy chain and beta-2-microglobulin was decreased in inhibitor treated C1R transfectants, suggesting that MTP-mediated lipid transfer in the ER is essential for proper folding and function of CD1 molecules on the cell surface and/or that in the absence of initial lipid association in the ER, endosomal lipid exchange by saposins and GM2 activator proteins might be impaired.

Conclusion: Our data implicate that the immune system has co-opted a key protein of lipid metabolism, MTP, for its antigen presentation pathways, and via MTP's regulation of CD1a, b, and c function, this protein has a key role in the host immune response toward microbial pathogens. This might have implications for mucosal inflammation in IBD, as CD1a, CD1b, and CD1c molecules are expressed on dendritic cells in the intestinal mucosa (unpublished observation, Per Brandtzaeg & RSB).

(AK and DLH contributed equally)