Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection

Rawson, Pisana; Molette, Caroline; Videtta, Melissa; Altieri, Laura; Franceschini, Debora; Donato, Tiziana; Finocchi, Luigi; Propato, Antonella; Paroli, Marino; Meloni, Francesca; Mastroianni, Claudio Maria; d’Ettorre, Gabriella; Sidney, John; Sette, Alessandro; Barnaba, Vincenzo

doi:10.1038/nm1679

Cited by 73 publications

(126 citation statements)

References 49 publications

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“…It has been shown that autoantigens can be generated by the collaborative efforts of activated caspases and proteasome, which may result in lymphodepletion in HIV-infected patients (33). Of note, various tumor cells express basal levels of caspase activities (23) or they transiently activate effector caspases without cell death (34).…”

Section: Discussionmentioning

confidence: 99%

Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis

Pang

Neijssen

Qiao

et al. 2009

The Journal of Immunology

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MHC class I molecules present peptides from endogenous proteins. Ags can also be presented when derived from extracellular sources in the form of apoptotic bodies. Cross-presentation of such Ags by dendritic cells is required for proper CTL responses. The fate of Ags in cells initiated for apoptosis is unclear as is the mechanism of apoptosis-derived Ag transfer into dendritic cells. Here we show that novel Ags can be generated by caspases and be presented by MHC class I molecules of apoptotic cells. Since gap junctions function until apoptotic cells remodel to form apoptotic bodies, transfer and cross-presentation of apoptotic peptides by neighboring and dendritic cells occurs. We thus define a novel phase in classical Ag presentation and cross-presentation by MHC class I molecules: presentation of Ags created by caspase activities in cells in apoptosis.

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Section: Discussionmentioning

confidence: 99%

Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis

Pang

Neijssen

Qiao

et al. 2009

The Journal of Immunology

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“…Indeed, comprehensive proteomic studies of human islets demonstrate that these 'housekeeping genes' are, without exception, expressed in islet cells [19,20]. In conjunction with the shared predominance of executioner caspases 3 and 8 during apoptosis induction in both cell types [18,21], we reasoned that similar peptide fragments are probably generated under apoptotic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…The caspase-cleaved apoptotic self-antigens used in this study have been reported previously by Rawson et al and were generated by apoptosis induction in HLA-A2-restricted, human CD95 + CD8 + T cell clones by treatment with a monoclonal antibody to CD95 [18]. The apoptotic cells were lysed and their proteome was compared to control cells using subtractive analysis by two-dimensional electrophoresis to identify modified proteins.…”

Section: Experimental Approach For the Analysis Of Apoptosis-associatmentioning

confidence: 99%

“…List of peptides used in this study. *IC50 indicates binding affinity for A*0201 and it is expressed as 50% inhibitory nanomolar concentration; peptides with IC50 <50 nM are classified as high affinity peptides, peptides with IC50 >50 nM are classified as intermediate affinity peptides, peptides with IC50 >500 nM were classified as low affinity peptides in the original study and were not resynthesized [18]. hnRNP K, heterogeneous nuclear ribonucleoprotein K; Rho GDI 2, Rho guanine nucleotide dissociation inhibitor-2.…”

Section: Supporting Informationmentioning

confidence: 99%

“…This mouse strain develops autoimmune diabetes analogous to the conventional NOD mouse, but has a CD8 T cell repertoire that recognizes islet epitopes similar to the ones found in T1D patients carrying the HLA-A0201 haplotype [7,17]. We have utilized a unique set of HLA-A0201-restricted peptides derived from ubiquitous structural cell proteins that are generated specifically under conditions of caspase activity in humans [18]. While Rawson and co-workers originally derived this peptide library from apoptotic CD8 T cells, all belong to ubiquitously expressed 'housekeeping genes' and can thus be found consistently within pancreatic islet cells [19,20].…”

Section: Introductionmentioning

confidence: 99%

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Incidental CD8 T cell reactivity against caspase-cleaved apoptotic self-antigens from ubiquitously expressed proteins in islets from prediabetic human leucocyte antigen-A2 transgenic non-obese diabetic mice

Coppieters

Amirian

Herrath

2011

Clinical and Experimental Immunology

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SummaryApoptosis is known as a major mechanism which contributes to beta cell decay in type 1 diabetes. Commitment to this pathway generally involves caspase-mediated protein cleavage and was found to induce crosspresentation of a specific antigen repertoire under certain inflammatory conditions. We aimed to assess the significance of the CD8 T cell population reactive against such caspase-cleaved apoptotic self-antigens in pancreatic islets of prediabetic human leucocyte antigen (HLA)-A2 transgenic non-obese diabetic chimeric monochain transgene construct (NOD.HHD) mice. We have reproduced a unique peptide library consisting of human CD8 T cellderived apoptosis-specific antigens, all of which belong to structural proteins expressed ubiquitously in human islets. Pancreatic islets from prediabetic NOD.HHD mice, harbouring humanized major histocompatibilty complex (MHC) class I, were isolated and handpicked at various ages, and isletinfiltrating CD8 T cells were expanded in vitro and used as responders in an interferon (IFN)-g enzyme-linked immunospot (ELISPOT) assay. Human T2 cells were used as antigen-presenting cells (APC) to avoid endogenous antigen presentation. Analogous to the interindividual variability found with peptides from known islet autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) and insulin, some mice showed variable, low-degree CD8 T cell reactivity against caspase-cleaved self-antigens. Because reactivity was predominantly minor and often undetectable, we conclude that beta cell apoptosis does not routinely provoke the development of dominant cytotoxic T lymphocyte (CTL) reactive against caspase-cleaved selfantigens in the NOD.HHD model.

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Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4⁺ T‐cell responses

et al. 2014

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Keywords: Apoptotic cells r CD4 + T-cell responses r Dendritic cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionOne of the key features of the immune system is to react to foreign pathogens and not respond to the self-antigens derived from dying cells that can be presented to the immune system in far greater amounts. Thymic selection removes the vast majority of developing thymocytes that express a T-cell receptor with high specificity for self-peptide: MHC complexes, a process referred to as central tolerance. Nevertheless, some self-reactive T cells are released into the periphery [1,2]. The mechanisms that control such potentially [25][26][27][28]. Moreover, in animal models, the use of apoptotic cells to prevent autoimmunity has also been reported [29,30]. DCs also possess the unique ability to induce proliferation of autologous T cells in the absence of exogenous antigen, a process termed "autologous mixed leukocyte reaction" [31]. T cells activated in this process display normal immune response [32] in terms of specificity and memory, and a capacity for immunosuppression [33][34][35][36]. There is evidence that, in this process, DCs present peptides derived from self-proteins [37], mostly derived from residual apoptotic cells [38,39]. However, the effect of the capture of apoptotic cells by DCs on their ability to stimulate and support the proliferation of naive autologous CD4 + T cells, and therefore to generate self-reactive responses, has never been studied in detail. Surprisingly, we found that DCs loaded with apoptotic cells induced a robust proliferation of autologous naive CD4 + T cells. These proliferating autologous CD4 + T cells exhibited suppressive phenotype and function, unless a TLR ligand mimicking concomitant infection was added to the apoptotic cell-DC culture, yielding Th17 differentiation. Results Robust autologous responses induced by apoptotic cell-loaded DCsIn order to examine the effect of apoptotic cell uptake by DCs on their ability to induce potential autologous CD4 + T-cell responses, we have set up an experimental procedure in which DCs were loaded with autologous apoptotic CD4 + T-cell blasts for 16 hours, purified, and cultured with autologous naive CD4 stimulated-CD4 + T cells were also able to induce proliferation of autologous naive CD4 + T cells, whereas DCs loaded with necrotic CD4 + T-cell blasts were not (Supporting Information Fig. 1). To understand whether this was due to a very few cells that have proliferated to high levels or whether this reflected an increase in the frequency of proliferative precursors, we used two different methods. The first was based on intracellular staining with the antibody specific for Ki67, which is strictly expressed only during cell proliferation ( Fig. 1B), but is absent from resting cells, making it a marker to determine the fraction of cells that will proliferate. This staining was performed on day 2, just before the beginning of the proliferation, and ...

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Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection

Cited by 73 publications

References 49 publications

Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis

Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis

Incidental CD8 T cell reactivity against caspase-cleaved apoptotic self-antigens from ubiquitously expressed proteins in islets from prediabetic human leucocyte antigen-A2 transgenic non-obese diabetic mice

Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4⁺ T‐cell responses

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Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection

Cited by 73 publications

References 49 publications

Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis

Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis

Incidental CD8 T cell reactivity against caspase-cleaved apoptotic self-antigens from ubiquitously expressed proteins in islets from prediabetic human leucocyte antigen-A2 transgenic non-obese diabetic mice

Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4+ T‐cell responses

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Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4⁺ T‐cell responses