The melting pot of the MHC II peptidome

Stern, Lawrence J.; Santambrogio, Laura

doi:10.1016/j.coi.2016.03.004

Cited by 35 publications

(30 citation statements)

References 108 publications

(97 reference statements)

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“…A total of 6116 distinct peptide sequences were identified in 5 samples of WT cells ( Fig. 2A, supplemental Table S1), similar to the numbers of peptides identified in recent high-density immunopeptidome studies for other human and mouse MHC proteins (61). A smaller number of peptides, 5207, was identified in samples from DO-KO-1 cells processed in parallel ( Fig.…”

Section: Generation and Validation Of Do-ko And Wt Clones-supporting

confidence: 76%

“…Binding Affinity and DM Sensitivity Measurements-For three abundant self-peptides, DM sensitivity has been previously characterized: CLIP, the invariant chain chaperone fragment efficiently removed by DM (18,54), DR␣ [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] , the human ortholog of the YAe epitope (55) known to be highly sensitive to DM exchange (56), and the transplantation alloepitope A2 104 -117 (39) previously demonstrated to be highly resistant to DM-mediated exchange (38). For these peptides, we summed the intensities of all peptides sharing the respective core epitopes and compared summed intensities between replicate samples of WT and DO-KO-1 cells.…”

Section: Generation Of Do-knockout (Do-ko)mentioning

confidence: 99%

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HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

Nanaware

Jurewicz

Leszyk

et al. 2019

Molecular & Cellular Proteomics

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In BriefComprehensive analysis of MHC-II immunopeptidomes from cells lacking DO (human HLA-DO or murine H2-O) shows that DO controls the diversity of the MHC-II peptide repertoire. DO expression leads to presentation of a broader distribution of peptides, with many low-abundance epitopes presented only in the presence of DO. We suggest that regulated expression of DO allows the immune system to maintain tolerance to a wide variety of self-antigens and allows for an immune response focused on immunodominant antigens for pathogen recognition. Highlights• MHC-II-bound peptide repertoires from DO-sufficient and DO-deficient cells.• Fewer unique peptides and core epitopes were presented in the absence of DO.• Immunopeptidome differences appeared to result from reduced DM editing.• DO-dependent self-epitopes elicited CD4 T cell responses in mice.

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Section: Generation and Validation Of Do-ko And Wt Clones-supporting

confidence: 76%

Section: Generation Of Do-knockout (Do-ko)mentioning

confidence: 99%

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

Nanaware

Jurewicz

Leszyk

et al. 2019

Molecular & Cellular Proteomics

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“…Transcriptional control of MHC-II expression may be a molecular basis of immune surveillance, through which APC functions are regulated by M. tuberculosis protein during infection (Ramachandra et al, 2009). Actually, MHC-II expression can be regulated by cytokines like IFN-γ or TLRs ligands in macrophages during MTB infection (Stern and Santambrogio, 2016). Some Mycobacterial lipoproteins such as (LpqH and LprG) were found to suppress MHC-II expression via TLR2 in macrophages (Stewart et al, 2005; Shukla et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Zhu

et al. 2016

Front. Cell. Infect. Microbiol.

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TLR2-dependent cellular signaling in Mycobacterium tuberculosis-infected macrophages causes apoptosis and inhibits class II major histocompatibility complex (MHC-II) molecules antigen processing, leading to evasion of surveillance. Mycobacterium tuberculosis (MTB) lipoproteins are an important class of Toll-like receptor (TLR) ligand, and identified as specific components that mediate these effects. In this study, we identified and characterized MTB lipoprotein Rv1016c (lpqT) as a cell wall associated-protein that was exposed on the cell surface and enhanced the survival of recombinants M. smegmatis_Rv1016c under stress conditions. We found that Rv1016c lipoprotein was a novel TLR2 ligand and able to induce macrophage apoptosis in a both dose- and time-dependent manner. Additionally, apoptosis induced by Rv1016c was reserved in THP-1 cells blocked with anti-TLR-2 Abs or in TLR2−/− mouse macrophages, indicating that Rv1016c-induced apoptosis is dependent on TLR2. Moreover, we demonstrated that Rv1016c lipoprotein inhibited IFN-γ-induced MHC-II expression and processing of soluble antigens in a TLR2 dependent manner. Class II transactivator (CIITA) regulates MHC II expression. In this context, Rv1016c lipoprotein diminished IFN-γ-induced expression of CIITA IV through TLR2 and MAPK Signaling. TLR2-dependent apoptosis and inhibition of MHC-II Ag processing induced by Rv1016c during mycobacteria infection may promote the release of residual bacilli from apoptotic cells and decrease recognition by CD4+ T cells. These mechanisms may allow intracellular MTB to evade immune surveillance and maintain chronic infection.

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“…Evidently, engineering APC to present epitopes from whole allergens is advantageous since most allergens contain several T cell epitopes. However, it is well established that MHC class II presented peptides are also generated outside of endosomes and it is thus possible that some epitopes might not survive processing in endosomes and would be lost upon targeting allergens into these compartments 35 36 .…”

Section: Discussionmentioning

confidence: 99%

Creation of an engineered APC system to explore and optimize the presentation of immunodominant peptides of major allergens

Rosskopf

Jutz

Neunkirchner

et al. 2016

Sci Rep

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We have generated engineered APC to present immunodominant peptides derived from the major aero-allergens of birch and mugwort pollen, Bet v 1142–153 and Art v 125–36, respectively. Jurkat-based T cell reporter lines expressing the cognate allergen-specific T cell receptors were used to read out the presentation of allergenic peptides on the engineered APC. Different modalities of peptide loading and presentation on MHC class II molecules were compared. Upon exogenous loading with allergenic peptides, the engineered APC elicited a dose-dependent response in the reporter T cells and the presence of chemical loading enhancers strongly increased reporter activation. Invariant chain-based MHC class II targeting strategies of endogenously expressed peptides resulted in stronger activation of the reporters than exogenous loading. Moreover, we used Bet v 1 as model allergen to study the ability of K562 cells to present antigenic peptides derived from whole proteins either taken up or endogenously expressed as LAMP-1 fusion protein. In both cases the ability of these cells to process and present peptides derived from whole proteins critically depended on the expression of HLA-DM. We have identified strategies to achieve efficient presentation of allergenic peptides on engineered APC and demonstrate their use to stimulate T cells from allergic individuals.

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The melting pot of the MHC II peptidome

Cited by 35 publications

References 108 publications

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

HLA-DO Modulates the Diversity of the MHC-II Self-peptidome

Recombinant Lipoprotein Rv1016c Derived from Mycobacterium tuberculosis Is a TLR-2 Ligand that Induces Macrophages Apoptosis and Inhibits MHC II Antigen Processing

Creation of an engineered APC system to explore and optimize the presentation of immunodominant peptides of major allergens

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