Forced Expression of HLA-DM at the Surface of Dendritic Cells Increases Loading of Synthetic Peptides on MHC Class II Molecules and Modulates T Cell Responses

Pezeshki, Abdul Mohammad; Côté, Marie Hélène; Azar, Georges A.; Routy, Jean Pierre; Boulassel, Mohamed Rachid; Thibodeau, Jacques

doi:10.4049/jimmunol.1002747

Cited by 11 publications

(7 citation statements)

References 46 publications

(67 reference statements)

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“…M1 macrophages also overexpressed HLA‐DM compared with M1 microglia. HLA‐DM plays a role in MHC peptide loading and has been shown to bias T‐cell differentiation towards the Th1 lineage (Pezeshki et al,2011). Our data suggest that regardless of polarization state, macrophages may play a more significant role than microglia in antigen presentation, with M1 macrophages more likely to bias Th1 responses.…”

Section: Discussionmentioning

confidence: 99%

Comparison of polarization properties of human adult microglia and blood‐derived macrophages

Durafourt

Moore

Zammit

et al. 2012

Glia

424

378

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Both microglia, the resident myeloid cells of the CNS parenchyma, and infiltrating blood-derived macrophages participate in inflammatory responses in the CNS. Macrophages can be polarized into M1 and M2 phenotypes, which have been linked to functional properties including production of inflammation association molecules and phagocytic activity. We compare phenotypic and functional properties of microglia derived from the adult human CNS with macrophages derived from peripheral blood monocytes in response to M1 and M2 polarizing conditions. Under M1 conditions, microglia and macrophages upregulate expression of CCR7 and CD80. M2 treatment of microglia-induced expression of CD209 but not additional markers CD23, CD163, and CD206 expressed by M2 macrophages. M1-polarizing conditions induced production of IL-12p40 by both microglia and macrophages; microglia produced higher levels of IL-10 under M1 conditions than did macrophages. Under M2 conditions, microglia 6 LPS produced comparable levels of IL-10 under M1 conditions whereas IL-10 was induced by LPS in M2 macrophages. Myelin phagocytosis was greater in microglia than macrophages under all conditions; for both cell types, activity was higher for M2 cells. Our findings delineate distinctive properties of microglia compared with exogenous myeloid cells in response to signals derived from an inflammatory environment in the CNS. V

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Section: Discussionmentioning

confidence: 99%

Comparison of polarization properties of human adult microglia and blood‐derived macrophages

Durafourt

Moore

Zammit

et al. 2012

Glia

424

378

View full text Add to dashboard Cite

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“…DM nevertheless is also found in all endocytic compartments where it is supposed to contribute to a greater or lower extent to peptide editing, and for some cell types even at the cell surface 63 . Although DM activity at the surface is usually ignored, it has been shown that overexpression of a mutant which is retained at the cell surface can indeed favor extracellular peptide biding 64 . Similarly, our recent description of a DM allotype with a considerably higher activity at neutral pH may have a significant impact on peptide editing at the cell surface 9 …”

Section: Peptide Editing By Hla‐dmmentioning

confidence: 99%

Revisiting nonclassical HLA II functions in antigen presentation: Peptide editing and its modulation

Álvaro-Benito

Freund

2020

HLA

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The nonclassical major histocompatibility complex of class II molecules (ncMHCII) HLA‐DM (DM) and HLA‐DO (DO) feature essential functions for the selection of the peptides that are displayed by classical MHCII proteins (MHCII) for CD4+ Th cell surveillance. Thus, although the binding groove of classical MHCII dictates the main features of the peptides displayed, ncMHCII function defines the preferential loading of peptides from specific cellular compartments and the extent to which they are presented. DM acts as a chaperone for classical MHCII molecules facilitating peptide exchange and thereby favoring the binding of peptide‐MHCII complexes of high kinetic stability mostly in late endosomal compartments. DO on the other hand binds to DM blocking its peptide‐editing function in B cells and thymic epithelial cells, limiting DM activity in these cellular subsets. DM and DO distinct expression patterns therefore define specific antigen presentation profiles that select unique peptide pools for each set of antigen presenting cell. We have come a long way understanding the mechanistic underpinnings of such distinct editing profiles and start to grasp the implications for ncMHCII biological function. DM acts as filter for the selection of immunodominant, pathogen‐derived epitopes while DO blocks DM activity under certain physiological conditions to promote tolerance to self. Interestingly, recent findings have shown that the unexplored and neglected ncMHCII genetic diversity modulates retroviral infection in mouse, and affects human ncMHCII function. This review aims at highlighting the importance of ncMHCII function for CD4+ Th cell responses while integrating and evaluating what could be the impact of distinct editing profiles because of natural genetic variations.

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“…However, the Neefjes laboratory demonstrated at the cellular level by Fö rsters resonance energy transfer (FRET) that DM-DR interaction is pH-independent [115]. Moreover, Thibodeau et al have also shown that DM indeed can catalyse peptide-exchange on the cell surface modulating T-cell responses [116]. It is worth noting that those studies were based on overexpression of the different MHC proteins under consideration and the physiological barriers to interaction may be overcome at high expression levels.…”

Section: Biochemical and Structural Insights Into The Function Of Hla-dmmentioning

confidence: 99%

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

Álvaro-Benito¹,

Morrison²,

Wieczorek³

et al. 2016

Open Biol.

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Classical MHC class II (MHCII) proteins present peptides for CD4+ T-cell surveillance and are by far the most prominent risk factor for a number of autoimmune disorders. To date, many studies have shown that this link between particular MHCII alleles and disease depends on the MHCII's particular ability to bind and present certain peptides in specific physiological contexts. However, less attention has been paid to the non-classical MHCII molecule human leucocyte antigen-DM, which catalyses peptide exchange on classical MHCII proteins acting as a peptide editor. DM function impacts the presentation of both antigenic peptides in the periphery and key self-peptides during T-cell development in the thymus. In this way, DM activity directly influences the response to pathogens, as well as mechanisms of self-tolerance acquisition. While decreased DM editing of particular MHCII proteins has been proposed to be related to autoimmune disorders, no experimental evidence for different DM catalytic properties had been reported until recently. Biochemical and structural investigations, together with new animal models of loss of DM activity, have provided an attractive foundation for identifying different catalytic efficiencies for DM allotypes. Here, we revisit the current knowledge of DM function and discuss how DM function may impart autoimmunity at the organism level.

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Forced Expression of HLA-DM at the Surface of Dendritic Cells Increases Loading of Synthetic Peptides on MHC Class II Molecules and Modulates T Cell Responses

Cited by 11 publications

References 46 publications

Comparison of polarization properties of human adult microglia and blood‐derived macrophages

Comparison of polarization properties of human adult microglia and blood‐derived macrophages

Revisiting nonclassical HLA II functions in antigen presentation: Peptide editing and its modulation

Human leukocyte Antigen-DM polymorphisms in autoimmune diseases

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