Regulation and trafficking of the HLA-E molecules during monocyte-macrophage differentiation

Abstract

HLA-E is a nonclassical HLA-class I molecule whose best known role is to protect from the natural killer cells. More recently, an additional function more similar to that of classical HLA-class I molecules, i.e., antigen presentation to T cells, is emerging. However, much remains to be explored about the intracellular trafficking of the HLA-E molecules. With the use of 3 different cellular contexts, 2 monocytic cell lines, U937 and THP1, and peripheral blood monocytes, we show here a remarkable increase of HLA-E during monocyte-macrophage differentiation. This goes independently from the classical HLA-class I, the main source of HLA-E-specific peptides, which is found strongly up-regulated upon differentiation of peripheral blood monocytes but not at all in the case of U937 and THP1 cell lines. Although in all cases, there was a moderate increase of HLA-E expressed in the cell surface, lysis by natural killer cells is comparably restored by an anti-NKG2A antibody in untreated as well as in PMA-differentiated U937 cells. Instead, the great majority of the HLA-E is retained in the vesicles of the autophagy-lysosome network, where they colocalize with the microtubule-associated protein light chain 3, as well as with the lysosomal-associated membrane protein 1. We conclude that differently from the classical HLA-class I molecules, the primary destination of the newly synthesized HLA-E molecules in macrophages is, rather than the cell membrane, the intracellular autophagy-lysosomal vesicles where they are stored and where they can encounter the exogenous antigens.

Broadly targeted CD8 + T cell responses restricted by major histocompatibility complex E

“…However, this evasion strategy would have the consequence of enhancing MHC-E expression in such infected cells, increasing the opportunity for loading and presentation of novel peptides to MHC-E-restricted T cells. In this regard, the canonical MHC-E-binding VL9 peptide might act as a chaperone that facilitates stable high expression of MHC-E and delivery to an endosomal compartment (26) that would facilitate peptide exchange, analogous to the invariant chain-associated CLIP peptide and MHC-II (1). The rigid, open structure of the MHC-E peptide binding groove would be expected to facilitate peptide exchange, consistent with this putative mechanism.…”

EBV Infection Empowers Human B Cells for Autoimmunity: Role of Autophagy and Relevance to Multiple Sclerosis

“…EBV infection could convert this tolerogenic mechanism into productive processing of the epitope. The peptide that survives the processing in autophagosomes is then loaded on HLA-E and presented to autoreactive CTLs facilitating autoimmunity (39).…”

Experimental autoimmune encephalomyelitis in the common marmoset: a translationally relevant model for the cause and course of multiple sclerosis

“…Mf is macrophage, TPPP is tubulin polymerization-promoting protein, ODC is oligodendrocyte. metabolic defect and subtle molecular changes (Caprariello et al, 2018), or an external cause, which could be associated with a Western lifestyle ('t Hart, 2016b) (see Box 4), an infection or a combination of all features. It is pertinent to emphasize, however, that our choice for the inside-out paradigm as a working concept does not negate the possibility that MS is triggered by an external factor.…”

“…Conceptually, the association of the MOG34-56 peptide with autophagosomes may explain the protection of the MOG40-48 epitope against fast degradation in lysosomes, which leads to enhanced immunogenicity (Delamarre et al, 2006) and facilitates cross-presentation (Munz, 2009). Moreover, evidence suggests that HLA-E localizes in autophagosomes, where uploading with the peptide could take place (Camilli et al, 2016). Collectively, these data provide a plausible novel explanation for the EBV-MS association and for the pathogenic role of the EBV-infected B cell.…”