Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection

Varanasi, Vineeth; Khan, Aly A.; Chervonsky, Alexander V.

doi:10.1073/pnas.1401750111

Cited by 11 publications

(12 citation statements)

References 45 publications

(62 reference statements)

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“…Consequently, we also did not observe a decrease in viral titers in mice that received transfer of Id3 RV-transduced P14 T cells. These findings are in agreement with other recent studies demonstrating that Fas 2 CD8 + T cells are more resistant to deletion, but Fas deficiency in CD8 + T cells does not prevent functional exhaustion (17). Thus, for therapeutic options in chronic infection, it is necessary to supplement targeting of the Id3-Fas axis with molecules that target T cell exhaustion to increase the abundance of functional T cells.…”

Section: Discussionsupporting

confidence: 92%

“…Importantly, Fas/FasL-mediated death contributes to the elimination of virus-specific CD8 + T cells in chronic LCMV infection in a T cell-intrinsic manner (17), yet the molecular mechanism of Fas/FasL-mediated cell death is complex. Although in some cases the absolute levels of Fas surface expression correlate well with susceptibility to FasL-mediated death (36), Fas membrane localization, efficiency of receptor signaling complex assembly and activation, and cross-talk with members of the intrinsic apoptosis pathway also influence susceptibility to FasLmediated death (37).…”

Section: Discussionmentioning

confidence: 99%

“…The Bimmediated intrinsic pathway controls both T cell contraction in acute infection and the persistence of Ag-specific CD8 + T cells in chronic infection (3,(10)(11)(12)(13)(14)(15). In acute infections, Fas/Fas ligand (FasL)-triggered cell death is dispensable for CD8 + T cell contraction (13,16); however, it could compensate for the loss of Bim in another infection model (14), and both Bim and Fas were shown to cooperate in controlling the cell death of Ag-stimulated CD8 + T cells in chronic infection (12,(17)(18)(19).…”

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confidence: 99%

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Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Menner

Rauch

Aichele

et al. 2015

The Journal of Immunology

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Sustained Ag persistence in chronic infection results in a deregulated CD8+ T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8+ T cells. Yet, the underlying transcriptional mechanisms regulating CD8+ T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8+ T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3− virus-specific CD8+ T cells were less abundant, whereas the absolute numbers of Id3+ virus-specific CD8+ T cells were equal in chronic and acute infection. Phenotypically, Id3− and Id3+ cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3− cells were 2B4+, almost all Id3+ cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3−2B4+ cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4+ virus-specific CD8+ T cells by decreasing susceptibility to Fas/Fas ligand–mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8+ T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8+ T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8+ T cells to prevent immunopathology.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Menner

Rauch

Aichele

et al. 2015

The Journal of Immunology

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“…Conversely, granzyme A upregulation with cytokines could be of importance in the control of viral and bacterial infections as unlike granzyme B, granzyme A can potently mediate cytolysis in the presence of caspase inhibitors (Blasche et al, 2013; Zhang, Beresford, Greenberg, & Lieberman, 2001) or alternatively, may aid in the inflammatory response as discussed previously (Kurioka et al, 2015). Additionally, both modes of activation result in the upregulation of FasL on the surface of MAIT cells; FasL is involved in death receptor-mediated killing of infected cells (Varanasi, Khan, & Chervonsky, 2014).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

Lamichhane

Schneider

Harpe

et al. 2019

Preprint

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8 9 3 1human MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond 3 2 to TCR stimulation through the production of multiple effector cytokines and chemokines, 3 3 alteration of their cytotoxic granule content and transcription factor expression, and upregulation 3 4 of co-stimulatory proteins CD40L and 4-1BB. In contrast, cytokine-mediated activation is slower 3 5and results in more limited production of cytokines, chemokines, and co-stimulatory proteins; 3 6 differences in granule content and transcription factor expression are also evident. Therefore, we 3 7 propose that in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in 3 8 effecting and coordinating the immune response, while in the absence of TCR stimulation (e.g. 3 9 viral infection) their role is likely to differ. 4 0 4 1

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“…Although the proapoptotic Bcl‐2 family member Bim is not a member of the CD95‐mediated apoptotic signaling pathway , this apoptotic factor contributes to the elimination of activated T lymphocytes in mice injected with the superantigen staphylococcal enterotoxin B (SEB). Therefore, while CD95 is involved in the elimination of activated T lymphocytes responding to weak auto‐Ags and Ags found in chronic infections , it is not involved in the elimination of T cells activated by high‐affinity Ags such as those found in acute infections.…”

Section: Cd95/cd95l As Regulators Of the Immune Cell Functionsmentioning

confidence: 99%

Nonapoptotic functions of Fas/CD95 in the immune response

Guégan

Legembre

2017

The FEBS Journal

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CD95 (also known as Fas) is a member of the tumor necrosis factor receptor (TNFR) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Mutations in this receptor are associated with a loss of apoptotic signaling and have been detected in an autoimmune disorder called autoimmune lymphoproliferative syndrome (ALPS) type Ia, which shares some clinical features with systemic lupus erythematosus (SLE). In addition, deletions and mutations of CD95 have been described in many cancers, which led researchers to initially classify this receptor as a tumor suppressor. More recent data demonstrate that CD95 engagement evokes nonapoptotic signals that promote inflammation and carcinogenesis. Transmembrane CD95L (m‐CD95L) can be cleaved by metalloproteases, releasing a soluble ligand (s‐CD95L). Soluble and membrane‐bound CD95L show different stoichiometry (homotrimer versus multimer of homotrimers, respectively), which differentially affects CD95‐mediated signaling through molecular mechanisms that remain to be elucidated. This review discusses the biological roles of CD95 in light of recent experiments addressing how a death receptor can trigger both apoptotic and nonapoptotic signaling pathways.

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Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection

Cited by 11 publications

References 45 publications

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Id3 Controls Cell Death of 2B4+ Virus-Specific CD8+ T Cells in Chronic Viral Infection

Transcriptional analysis defines TCR and cytokine-stimulated MAIT cells as rapid polyfunctional effector T cells that can coordinate the immune response

Nonapoptotic functions of Fas/CD95 in the immune response

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