Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning

Jiang, Wei; Adler, Lital N.; Macmillan, Henriette; Mellins, Elizabeth

doi:10.1038/s41598-019-50455-y

Cited by 16 publications

(26 citation statements)

References 63 publications

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“…DM is known as the class II "peptide editor" because of its roles in removing class II invariant chain peptide (CLIP) and promoting immunodominant epitope selection [4,5]. Similar to DM, DO is also an α/β heterodimer that does not bind peptides, but unlike DM, which first appeared in amphibians, DO was found only in warm-blooded mammals [6] and has restricted expression to thymic medulla, B cells [7][8][9], and certain dendritic cell subsets [10][11][12]. This limited tissue distribution, late evolutionary appearance, and regulated expression of DO suggests that DO might have important regulatory effects on the selection of epitopes presented by MHC II during thymic deletion and B cell antigen presentation.…”

Section: Introductionmentioning

confidence: 99%

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

et al. 2020

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DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and wholebody imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development. Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.org/10.1371/journal.pbio.3000590 February 18, 2020 3 / 29Fig 2. Naïve DO-KO mice have an expanded CD4 T-cell compartment as well as increased expression of Tregs. (A) Breakdown of T-cell compartment in the spleens of naïve DO-WT (white) and DO-KO (red) mice. N = 8 mice per group. Data are represented as mean ± SEM. (B). Subdivision of the CD4 T-cell compartment showed that DO-KO mice have increased percentage of CD4 + CD25 + -expressing cells. N = 8 mice per group. Data are represented as mean ± SEM. (C). Naïve expression of the Foxp3 transcription factor in naïve CD4 + T cells from DO-WT (white) and DO-KO (red) mice. N = 21 mice per group. Experimental results depicted in this figure can be found in S2 Data. Data are represented as mean ± SEM. DO, HLA-DO; Foxp3, forkhead box P3; KO, knockout; Treg, regulatory T cell; WT, wild-type. https://doi.org/10.1371/journal.pbio.3000590.g002 Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.org/10.1371/journal.pbio.3000590 February 18, 2020 5 / 29 mice. (A) Representative curves showing the time course of disease development in DO-KO (red) and DO-WT mice (white). N = 5 mice per group, representative of >15 repeat experiments. Score system: 0 = no symptoms, 1 = limp tail, 2 = limp tail + partial hind limb paralysis, 3 = limp tail + total Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.EAE was induced as previously described in both DO-WT and DO-KO mice. Mice were humanely killed on Day 17 of disease, brains and spinal columns were pooled, and infiltrating Lack of the MHC Class II chaperone H-2O causes susceptibility to autoimmune diseases PLOS Biology | https://doi.

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Section: Introductionmentioning

confidence: 99%

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

et al. 2020

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“…Since antigen-experienced B cells of animals with autoimmunity function as APCs, and may spontaneously drive TLS formation, these interactions result in CNS targeting and T cell mediated cytotoxicity in both neuroimmune disease models and human patients, resulting in neuropathology. Further support for B cell function as APCs in OMAS comes from the increased frequency in OMAS of HLA-DOB*01, an HLA allele expressed predominantly in B cells that modulates presentation of immunodominant epitopes (reviewed in Welsh and Sadegh-Nasseri, 2020; Jiang et al 2019). Finally, the observation of B cell trafficking, TLS- promoting chemokines in OMAS support the central role of B cells in TLS prevalence and B cell- T cell interactions accompanying both positive tumor outcomes and neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Rosenberg

Greenstein

Buchkovich

et al. 2021

Preprint

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Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop Opsoclonus Myoclonus Ataxia Syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity, but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor infiltrating T- and B-cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS associated neuroblastomas. We found greater B- and T-cell infiltration in OMAS-associated tumors compared to controls, but unexpectedly showed that both were polyclonal expansions. Tertiary lymphoid structures (TLS) were enriched in OMAS-associated tumors. We identified significant enrichment of the MHC Class II allele HLA-DOB*01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal autoreactive B lymphocytes act as antigen presenting cells and drive TLS formation, thereby crucially supporting both sustained polyclonal T-cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

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“…The T2DR4DMDO++ [medium level of DO:DM, or (DO:DM) M ] and T2DR4DMDO+++ [high level of DO:DM, or (DO:DM) H ] clonal lines were constructed by fluorescence-activated cell sorting (FACS) of the parental, polyclonal T2DR4DMDO transfectant for single cells with low (e.g., 1C3) or high (e.g., 2D7) levels of surface CLIP/DR4 complexes (17). FACS-sorted single clones were then expanded in a well of a 96-well plate to establish stable, single clonal lines, including 1C3 and 2D7, as described (17). To construct T2DR4DMDO+ [low level of DO:DM, or (DO:DM) L ], a plasmid pBudCE4.1-DOA/DOB_Gly 8 -linker_FLAG-tag was constructed similarly to the construction of pBudCE4.1-DOA/DOB.…”

Section: Cell Line Constructionmentioning

confidence: 99%

“…Acid-driven DO denaturation from DMDO complexes elevates free DM levels, thereby promoting the formation of stable pMHC-II (21). For instance, when the B cell receptor (BCR) binds antigen, B cell activation leads to acidification of late endosomes and denatures DO (17,51) This process is BCR-antigen affinity dependent (17).…”

Section: Strategy For Investigating the Influence Do:dm Has On Pmhc-ii Repertoiresmentioning

confidence: 99%

“…Longer peptides could also provide more alternative binding registers. In addition, increased free DM likely allows peptide exchange in earlier, less acidic endosomal compartments where different/reduced processing capacity may result in longer peptides; these are compartments where DO, when present, effectively inhibits DM (17). The length changes mediated by DO:DM can also affect T cell recognition and peptide immunogenicity (60)(61)(62).…”

Section: Pmhc-ii Characteristics Contribute To Do:dm-tuned Peptide Presentationmentioning

confidence: 99%

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Tuning DO:DM ratios modulates MHC class II immunopeptidomes

Olsson

Jiang

Adler

et al. 2021

Preprint

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Major histocompatibility complex class II (MHC-II) antigen presentation underlies a wide range of immune responses in health and disease. However, how MHC-II antigen presentation is regulated by the peptide-loading catalyst HLA-DM (DM), its associated modulator, HLA-DO (DO), is incompletely understood. This is due largely to technical limitations: model antigen presenting cell (APC) systems that express these MHC-II peptidome regulators at physiologically variable levels have not been described. Likewise, computational prediction tools that account for DO and DM activities are not presently available. To address these gaps, we created a panel of single MHC-II allele, HLA-DR4-expressing APC lines that cover a wide range of DO:DM ratio states. Using a combined immunopeptidomic and proteomic discovery strategy, we measured the effects DO:DM ratios have on peptide presentation by surveying over 10,000 unique DR4-presented peptides. The resulting data provide insight into peptide characteristics that influence their presentation with increasing DO:DM ratios. These include DM-sensitivity, peptide abundance, binding affinity and motif, peptide length and register positioning on the source protein. These findings have implications for designing improved HLA-II prediction algorithms and research strategies for dissecting the variety of functions that different APCs serve in the body.

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Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning

Cited by 16 publications

References 63 publications

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Tuning DO:DM ratios modulates MHC class II immunopeptidomes

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