Human Immunodeficiency Virus-1 Inhibition of Immunoamphisomes in Dendritic Cells Impairs Early Innate and Adaptive Immune Responses

Blanchet, Fabien P.; Moris, Arnaud; Nikolic, Damjan S.; Lehmann, Martin; Cardinaud, Sylvain; Stalder, Romaine; Garcia, Eduardo; Dinkins, Christina; Leuba, Florence; Wu, Li; Schwartz, Olivier; Deretic, Vojo; Piguet, Vincent

doi:10.1016/j.immuni.2010.04.011

Cited by 251 publications

(277 citation statements)

References 84 publications

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“…[10][11][12] MHC class II extracellular antigen processing by dendritic cells is also affected by macroautophagy. 13,14 The requirement found for further processing of precursors of epitope F249-258 may in fact point to a lysosomal or autophagy pathway. In general, autophagy supplies cytoplasmic components to lysosomes for their degradation.…”

Section: Resultsmentioning

confidence: 99%

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

et al. 2012

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Respiratory syncytial virus causes lower respiratory tract infections in infancy and old age, affecting also immunocompromised patients. The viral fusion protein is an important vaccine candidate eliciting antibody and cell-mediated immune responses. CD8 þ cytotoxic T lymphocytes (CTLs) are known to have a role in both lung pathology and viral clearance. In BALB/c mice, the fusion protein epitope F249-258 is presented to CTLs by the murine major histocompatibility complex (MHC) class I molecule K d . In cells infected with recombinant vaccinia viruses encoding the fusion protein, F249-258 is presented by MHC class I molecules through pathways that are independent of the transporters associated with antigen processing (TAP). We have now found that F249-258 can be generated from non-infectious virus from an exogenous source. Antigen processing follows a lysosomal pathway that appears to require autophagy. As a practical consequence, inactivated virus suffices for in vivo priming of virus-specific CTLs. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants and young children, 3 affecting also immunocompromised patients and the elderly. The fusion (F) glycoprotein of RSV is a major vaccine candidate as it is an important target for neutralising antibodies 4 and virus-specific CTLs. 5 Studies in the mouse model of human RSV have shown that CTLs have a role both in lung pathology and viral clearance. 6,7 In previous studies,

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Section: Resultsmentioning

confidence: 99%

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

et al. 2012

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“…A recent study also shows that HIV-1 can impair innate immune function by mTOR-mediated impaired autophagy of DCs [32]. The limited immune response seen in the early events of HIV-1 trans- Overview of the PI3K/PTEN/mTOR pathway depicting the sites of action of various inhibitors that result in the regulation of protein translation.…”

Section: Mtor and Impaired Function Of Innate Immunity During Hiv Infmentioning

confidence: 99%

“…www.drugdiscoverytoday.com 717 mission could result from the shutdown of autophagy and immunoamphisomes in DCs that rely on mTOR-dependent pathways [32]. HIV-1-induced inhibition of autophagy in DCs increases cellassociated HIV-1 and transfer of HIV-1 infection to CD4 + T cells.…”

Section: Mtor and Impaired Function Of Innate Immunity During Hiv Infmentioning

confidence: 99%

“…HIV-1-and mTOR-mediated downregulation of autophagy in DCs impaired innate and adaptive immune responses. Immunoamphisomes in DCs engulf incoming opportunistic infections and amplify pathogen degradation as well as Toll-like receptor responses and antigen presentation [32]. The findings that HIV-1 downregulates autophagy and impedes immune functions of DCs in an mTOR-dependent manner could have therapeutic and prophylactic implications for the use of specific mTOR inhibitors.…”

Section: Mtor and Impaired Function Of Innate Immunity During Hiv Infmentioning

confidence: 99%

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mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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“…Indeed in several studies MHC class I restricted antigen recognition was actually used as a control and no effect of macroautophagy inhibition on CD8 + T cell recognition was observed 26,36,43 . However, under certain circumstances macroautophagy might enhance antigen presentation on MHC class I molecules to CD8 + T cells, and we will summarize the so far sparse evidence for this here.…”

Section: Macroautophagy In Antigen Processing For Mhc Class I Presentmentioning

confidence: 99%

MHC presentation via autophagy and how viruses escape from it

Gannagé

Münz

2010

Semin Immunopathol

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T cells detect infected and transformed cells via antigen presentation by major histocompatibility complex (MHC) molecules on the cell surface. For T cell stimulation, these MHC molecules present fragments of proteins that are expressed or taken up by the cell. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8(+) and on MHC class II molecules to helper CD4(+) T cells. Proteasomes are primarily involved in MHC class I ligand and lysosomes, in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape and could maybe be harnessed for immunotherapy. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8 + and on MHC class II molecules to helper CD4 + T cells.Proteasomes are primarily involved in MHC class I ligand, and lysosomes in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes, and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape, and could maybe be harnessed for immunotherapy. Gannage and Münz 3

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Human Immunodeficiency Virus-1 Inhibition of Immunoamphisomes in Dendritic Cells Impairs Early Innate and Adaptive Immune Responses

Cited by 251 publications

References 84 publications

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

mTOR as a multifunctional therapeutic target in HIV infection

MHC presentation via autophagy and how viruses escape from it

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