Functional Avidity–Driven Activation-Induced Cell Death Shapes CTL Immunodominance

Santa, Silvia Dalla; Merlo, Anna; Bobisse, Sara; Ronconi, Elisa; Boldrin, Daniela; Milan, Gabriella; Barbieri, Vito; Marin, Oriano; Facchinetti, Antonella; Biasi, Giovanni; Dolcetti, Riccardo; Zanovello, Paola; Rosato, Antonio

doi:10.4049/jimmunol.1303203

Cited by 7 publications

(4 citation statements)

References 42 publications

(44 reference statements)

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“…The idea of "reverse immunoediting" firstly stemmed from the analysis of immunodominance (ID) in a retrovirus-induced tumor model [2]. In this study, we observed an unexpected immunodominance hierarchy in favor of lower avidity responding T cells ( Fig.…”

Section: How Viruses Can Sculpture the Immune Responsementioning

confidence: 65%

Reverse immunoediting: When immunity is edited by antigen

et al. 2016

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Immune selective pressure occurring during cancer immunoediting shapes tumor features revealed at clinical presentation. However, in the "Escape" phase, the tumor itself has the chance to influence the immunological response. Therefore, the capacity of the immune response to sculpt the tumor characteristics is only one side of the coin and even the opposite is likely true, i.e. that an antigen can shape the immune response in a sort of "reverse immunoediting". This reciprocal modeling probably occurs continuously, whenever the immune system encounters a tumor/foreign antigen, and can be operative in the pathogen/immune system interplay, thus possibly permeating the protective immunity as a whole. In line with this view, the characterization of a T cell response as well as the design of both active and passive immunotherapy strategies should also take into account all Ag features (type, load and presentation). Overall, we suggest that the "reverse immunoediting" hypothesis could help to dissect the complex interplay between antigens and the immune repertoire, and to improve the outcome of immunotherapeutic approaches, where T cell responses are manipulated and reprogrammed.

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Section: How Viruses Can Sculpture the Immune Responsementioning

confidence: 65%

Reverse immunoediting: When immunity is edited by antigen

et al. 2016

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“…The APCs will process and present this de novo expressed gp70 via the endogenous route, and, in this context, immunodominant viral antigen epitopes will be presented by a large number of APCs resulting in the induction of anergy or clonal deletion of most gp70specific CD8 + T cells, probably through activation-induced exhaustion of the majority of high affinity TCR T cells. 48 The residual surviving gp70-AH1-specific T cells, detected by ELISPOT and tetramer staining (Fig. 8a,b), are probably low-affinity clones, likely to be overcome during immune response amplification by different and more Sp6-specific tumour antigens.…”

Section: Discussionmentioning

confidence: 96%

“…A synergic stimulus for gp70 expression may be elicited by virus particles discharged by the CTL-lysed cells that may superinfect resident APCs. The APCs will process and present this de novo expressed gp70 via the endogenous route, and, in this context, immunodominant viral antigen epitopes will be presented by a large number of APCs resulting in the induction of anergy or clonal deletion of most gp70-specific CD8 + T cells, probably through activation-induced exhaustion of the majority of high affinity TCR T cells 48. The residual surviving gp70-AH1-specific T cells, detected by ELISPOT and tetramer staining (Fig 8a,b…”

Section: Discussionmentioning

confidence: 99%

Autologous cellular vaccine overcomes cancer immunoediting in a mouse model of myeloma

et al. 2015

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In the Sp6 mouse plasmacytoma model, a whole-cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced anatomically localized and cytotoxic T cell (CTL) -mediated protection against wild-type (WT) Sp6. Both WT Sp6 and Sp6/B7 showed down-regulated expression of MHC H-2 Ld. Increase of H-2 Ld expression by cDNA transfection (Sp6/B7/Ld) raised tumour immune protection and shifted most CTL responses towards H-2 Ld-restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 Ld-restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naive mice, were detected in immunized mice as well as in splenocytes from naive mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage-associated molecular patterns (DAMPs). It has been shown that Toll-like receptor triggering induces gp70 expression. Damage-associated molecular patterns are released by CTL-mediated killing of Sp6/B7-Sp6/B7/Ld cells migrated to draining lymph nodes during immunization and may activate gp70 expression and presentation in most resident antigen-presenting cells. The same could also apply for Mus musculus endogenous ecotropic murine leukaemia virus 1 particles present in Sp6-cytosol, discharged by dying cells and superinfecting antigen-presenting cells. The outcome of such a massive gp70 cross-presentation would probably be tolerogenic for the high-affinity AH1-gp70-specific CTL clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost.

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“…The tetramer staining intensity reflecting TCR avidity has been described as a marker for functional T cells. In detail, high tetramer binding T cells have been shown to be associated with high levels of cytotoxicity (16), high sensitivity to activation-induced cell death (17,18), senescence (19), and exhaustion (20,21). In contrast, low tetramer binding CMV T EMRA CTLs have been shown to accumulate in elderly CMV-seropositive individuals and to be associated with low effector function (22).…”

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confidence: 99%

Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation

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Verma

Schultze-Florey

et al. 2017

The Journal of Immunology

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CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tet CTLs) and high tetramer binding (CMV tet CTLs) in 53/115 CMV IgG patients stem cell transplanted from CMV IgG donors. However, the relevance of these coappearing differentially tetramer binding ("dual") CMV-CTLs was unclear. In this study, we investigated the kinetics, properties, and clinical impact of coappearing CMV tet and tet CTLs after allogeneic SCT. Patients with dual CMV-CTLs had more CMV tet than tet CTLs. Chimerism analysis of isolated CMV tet and tet CTLs revealed their exclusive donor origin. CMV tet and tet CTLs had an identical effector memory CD45RACCR7 and CD45RACCR7 T cell distribution, equal differentiation, senescence, and exhaustion marker expression and were negative for regulatory CD8 T cell markers. Isolated CMV tet and tet CTLs were equally sensitive to CMV peptides in IFN-γ release and cytotoxicity assays. However, CMV tet CTLs proliferated more in response to low CMV peptide concentrations than tet CTLs. TCR repertoire analysis revealed that CMV tet and tet CTLs use different TCRs. Finally, dual CMV-CTLs were not associated with CMV antigenemia. In conclusion, these data show for the first time, to our knowledge, that both CMV tet and tet CTLs are functional effector T cells differing by proliferation, numbers in peripheral blood, and probably by their precursors without increasing the CMV reactivation risk after allogeneic SCT.

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Functional Avidity–Driven Activation-Induced Cell Death Shapes CTL Immunodominance

Cited by 7 publications

References 42 publications

Reverse immunoediting: When immunity is edited by antigen

Reverse immunoediting: When immunity is edited by antigen

Autologous cellular vaccine overcomes cancer immunoediting in a mouse model of myeloma

Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation

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