Distinct Protease Requirements for Antigen Presentation In Vitro and In Vivo

Matthews, S.; Werber, Ingrid; Deussing, Jan M.; Peters, Christoph; Reinheckel, Thomas; Watts, Colin

doi:10.4049/jimmunol.0901486

Cited by 45 publications

(51 citation statements)

References 52 publications

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“…To determine if anti-TNF-fused peptides can be presented on the surface of DCs and can initiate an immune response, we fused 2 tetanus toxin (TT) peptides 38 at the C-terminal heavy chains of a humanized anti-TNF (anti-TNF-TT fusion IgG; Fig. 6A).…”

Section: Resultsmentioning

confidence: 99%

Transmembrane TNF-dependent uptake of anti-TNF antibodies

Deora

Hegde

Lee

et al. 2017

mAbs

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TNF-α (TNF), a pro-inflammatory cytokine is synthesized as a 26 kDa protein, anchors in the plasma membrane as transmembrane TNF (TmTNF), and is subjected to proteolysis by the TNF-α converting enzyme (TACE) to release the 15 kDa form of soluble TNF (sTNF). TmTNF and sTNF interact with 2 distinct receptors, TNF-R1 (p55) and TNF-R2 (p75), to mediate the multiple biologic effects of TNF described to date. Several anti-TNF biologics that bind to both forms of TNF and block their interactions with the TNF receptors are now approved for the treatment of a variety of immune-mediated diseases. Several reports suggest that binding of anti-TNFs to TmTNF delivers an outside-to-inside ‘reverse’ signal that may also contribute to the efficacy of anti-TNFs. Some patients, however, develop anti-TNF drug antibody responses (ADA or immunogenicity). Here, we demonstrate biochemically that TmTNF is transiently expressed on the surface of lipopolysaccharide-stimulated primary human monocytes, macrophages, and monocyte-derived dendritic cells (DCs) and expression of TmTNF on the cell surface is enhanced following treatment of cells with TAPI-2, a TACE inhibitor. Importantly, binding of anti-TNFs to TmTNF on DCs results in rapid internalization of the anti-TNF/TmTNF complex first into early endosomes and then lysosomes. The internalized anti-TNF is processed and anti-TNF peptides can be eluted from the surface of DCs. Finally, tetanus toxin peptides fused to anti-TNFs are presented by DCs to initiate T cell recall proliferation response. Collectively, these observations may provide new insights into understanding the biology of TmTNF, mode of action of anti-TNFs, biology of ADA response to anti-TNFs, and may help with the design of the next generation of anti-TNFs.

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Section: Resultsmentioning

confidence: 99%

Transmembrane TNF-dependent uptake of anti-TNF antibodies

Deora

Hegde

Lee

et al. 2017

mAbs

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“…BMM were fully adherent and were F4/80 positive by day 8. BMM from AEP KO mice (32) and Ii KO mice (kind gift of Dr. Liz Bikoff) were grown as described above.…”

Section: Methodsmentioning

confidence: 99%

Internalization of Exogenous Cystatin F Supresses Cysteine Proteases and Induces the Accumulation of Single-chain Cathepsin L by Multiple Mechanisms

Colbert

Matthews

Kos

et al. 2011

Journal of Biological Chemistry

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Background: Cystatin F is a protease inhibitor normally found within the endocytic pathway, but can be secreted.Results: Secreted cystatin F can be internalized thereby inhibiting multiple targets and causing the accumulation of cathepsin L.Conclusion: Cystatin F inhibits the CatL convertase AEP and stabilizes CatL protein levels.Significance: Secreted cystatin F can be activated in trans expanding its inhibitory potential beyond its site of synthesis.

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“…Instead the serine protease CatG was involved in antigen processing of both primary human B cells and mDC1 [76][77][78]. Conversely, AEP is expressed in primary human mDC2 and pDC [79] and low levels of AEP, found in primary murine DC, were sufficient in tetanus toxin C fragment processing [80]. These results underline the importance of using primary cells and different subsets of APC in experiments, in contrast to cell lines, and the need for further studies addressing (pro)-insulin-processing, including the concerted actions of primary human APCderived lysosomal cathepsins in (pro)-insulin digestion.…”

Section: T Cell Epitopesmentioning

confidence: 99%

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

Burster

Boehm

2010

Diabetes Metabolism Res

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SummaryBoth CD4 + and CD8 + T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4 + T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells.

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Distinct Protease Requirements for Antigen Presentation In Vitro and In Vivo

Abstract: MaterialSupplementary http://www.jimmunol.org/content/suppl/2010/02/17/184.5.2423.DC1

Cited by 45 publications

References 52 publications

Transmembrane TNF-dependent uptake of anti-TNF antibodies

Transmembrane TNF-dependent uptake of anti-TNF antibodies

Internalization of Exogenous Cystatin F Supresses Cysteine Proteases and Induces the Accumulation of Single-chain Cathepsin L by Multiple Mechanisms

Processing and presentation of (pro)‐insulin in the MHC class II pathway: the generation of antigen‐based immunomodulators in the context of type 1 diabetes mellitus

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