The elucidation of non-classical MHC class II antigen processing through the study of viral antigens

Ganesan, Asha Purnima Veerappan; Eisenlohr, Laurence C.

doi:10.1016/j.coviro.2016.11.009

Cited by 20 publications

(17 citation statements)

References 73 publications

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“…Recent findings even show a direct loading of MHCII molecules in the ER and Golgi supported by alternative chaperones as described below 30 . Overall, a very attractive, and perhaps more realistic picture of MHCII antigen presentation will include interconnections between all these different routes and processes as proposed by the Eisenlohr lab for viral infections 31,32 (Figure 1D).…”

Section: General Mechanisms Of Antigen Presentation By Mhcii Moleculesmentioning

confidence: 86%

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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Section: General Mechanisms Of Antigen Presentation By Mhcii Moleculesmentioning

confidence: 86%

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

Álvaro-Benito

Freund

2020

HLA

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“…Following proteolytic cleavage, these processed peptides displace CLIP on recycled MHC-II molecules, which are then transported to the cell surface for presentation to CD4 + T cells. However, considerable evidence has accumulated, suggesting that alternative pathways exist that allows cells to directly present cytosolic proteins on MHC-II (46). For example, a recent report found that dendritic cells infected with modified VacV Ankara presented MHC-II-restricted peptides from an endogenous presentation pathway to CD4 + T cells, a process that required functional proteasomes and autophagy (47).…”

Section: Discussionmentioning

confidence: 99%

Vaccinia Virus Vectors Targeting Peptides for MHC Class II Presentation to CD4+ T Cells

et al. 2020

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CD4+ helper T cells play important roles in providing help to B cells, macrophages, and cytotoxic CD8+ T cells, but also exhibit direct effector functions against a variety of different pathogens. In contrast to CD8+ T cells, CD4+ T cells typically exhibit broader specificities and undergo less clonal expansion during many types of viral infections, which often makes the identification of virus-specific CD4+ T cells technically challenging. In this study, we have generated recombinant vaccinia virus (VacV) vectors that target I-Ab–restricted peptides for MHC class II (MHC-II) presentation to activate CD4+ T cells in mice. Conjugating the lymphocytic choriomeningitis virus immunodominant epitope GP61–80 to either LAMP1 to facilitate lysosomal targeting or to the MHC-II invariant chain (Ii) significantly increased the activation of Ag-specific CD4+ T cells in vivo. Immunization with VacV-Ii-GP61–80 activated endogenous Ag-specific CD4+ T cells that formed memory and rapidly re-expanded following heterologous challenge. Notably, immunization of mice with VacV expressing an MHC-II–restricted peptide from Leishmania species (PEPCK335–351) conjugated to either LAMP1 or Ii also generated Ag-specific memory CD4+ T cells that underwent robust secondary expansion following a visceral leishmaniasis infection, suggesting this approach could be used to generate Ag-specific memory CD4+ T cells against a variety of different pathogens. Overall, our data show that VacV vectors targeting peptides for MHC-II presentation is an effective strategy to activate Ag-specific CD4+ T cells in vivo and could be used to study Ag-specific effector and memory CD4+ T cell responses against a variety of viral, bacterial, or parasitic infections.

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“…However, TAPL may have a more specialized function in professional antigen-presenting cells, in which its expression is strongly upregulated (Demirel et al, 2007 ). There are alternative pathways of endogenous antigens for processing and loading on MHC II (Veerappan Ganesan and Eisenlohr, 2017 ). One of these pathways is proteasome dependent but TAP-independent (Dani et al, 2004 ; Miller et al, 2015 ; Thiele et al, 2015 ).…”

Section: Physiological Functionmentioning

confidence: 99%

Moving the Cellular Peptidome by Transporters

Abele

Tampé

2018

Front. Cell Dev. Biol.

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Living matter is defined by metastability, implying a tightly balanced synthesis and turnover of cellular components. The first step of eukaryotic protein degradation via the ubiquitin-proteasome system (UPS) leads to peptides, which are subsequently degraded to single amino acids by an armada of proteases. A small fraction of peptides, however, escapes further cytosolic destruction and is transported by ATP-binding cassette (ABC) transporters into the endoplasmic reticulum (ER) and lysosomes. The ER-resident heterodimeric transporter associated with antigen processing (TAP) is a crucial component in adaptive immunity for the transport and loading of peptides onto major histocompatibility complex class I (MHC I) molecules. Although the function of the lysosomal resident homodimeric TAPL-like (TAPL) remains, until today, only loosely defined, an involvement in immune defense is anticipated since it is highly expressed in dendritic cells and macrophages. Here, we compare the gene organization and the function of single domains of both peptide transporters. We highlight the structural organization, the modes of substrate binding and translocation as well as physiological functions of both organellar transporters.

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The elucidation of non-classical MHC class II antigen processing through the study of viral antigens

Cited by 20 publications

References 73 publications

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

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

Vaccinia Virus Vectors Targeting Peptides for MHC Class II Presentation to CD4+ T Cells

Moving the Cellular Peptidome by Transporters

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