The Ins and Outs of Intracellular Peptides and Antigen Presentation by MHC Class I Molecules

Groothuis, Tom A.M.; Neefjes, Jacques

doi:10.1007/3-540-28007-3_6

Cited by 16 publications

(19 citation statements)

References 80 publications

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“…In addition to MHC molecules, other factors involved in antigen processing, such as TAP and the lysosomal membrane permeabilization components of proteasomes are regulated by IFN. Thus, IFNAR-triggering promotes the switch from proteasome to immuno-proteasome [36,37].In a previous study, we found in an in vitro setting that MVA infection can enhance expression of activation markers and costimulatory molecules on DC, whereas VACV infection effectively inhibited DC activation [16]. Here, we additionally demonstrated that MVA infection induced IFNAR-dependently co-stimulation in vivo that in turn indirectly influenced T-cell priming and expansion of CD8 1 T cells.…”

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confidence: 57%

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Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

et al. 2010

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Clinical Infection Research; a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Braunschweig; Hannover, Germany Virus-induced expansion of CD8 1 T cells may be promoted by type I IFN receptor (IFNAR)-triggering of T cells, depending on the pathogen tested. We studied modified vaccinia virus Ankara (MVA), a promising vaccine vector candidate, which was derived from conventional vaccinia virus (VACV) by more than 570 consecutive in vitro passages. In adoptive transfer experiments, we verified that VACV expressing the gp33 epitope of lymphocytic choriomeningitis virus (VACV gp33 ) induced largely IFNAR-independent expansion of gp33-specific T cells. On the contrary, MVA gp33 -induced T-cell expansion was IFNAR dependent. Interestingly, under the latter conditions, T-cell activation was IFNAR independent, whereas T-cell apoptosis was enhanced in the absence of IFNAR. To address whether MVA-induced T-cell expansion was solely affected by IFNAR-triggering of T cells, expansion of endogenous T cells was studied in conditional mice with a T-cell-or DC-specific IFNAR deletion. Interestingly, both mouse strains showed moderately reduced T-cell expansion, whereas mice with a combined T-cell-and DC-specific IFNAR ablation showed massively reduced T-cell expansion similar to that of IFNAR À/À mice. These results are compatible with the model that IFN-inducing viruses such as MVA confer virus-specific CD8 1 T-cell expansion by concomitant IFNAR-triggering of DC and of T cells.Key words: CD8 1 T-cell expansion . Modified vaccinia virus Ankara . Type I IFN IntroductionInfection with many different viruses induces rapid type I IFN responses that are detectable in serum within hours. IFN constitutes a family of cytokines with 14 IFN-a, one IFN-b subtype, and a number of other subclasses including . All IFN bind to one common heterodimeric receptor consisting of an a-chain (type I IFN receptor, IFNAR1) and a b-chain (IFNAR2). IFNAR-triggering results in phosphorylation of STAT1 and STAT2 transcription factors and the induction of at least 200 different target genes [2,3]. Although most cell lines show IFN expression upon in vitro infection, [7][8][9]. In particular, several studies reported IFN-mediated effects on T-cell responses [10,11]. In one report, lack of direct IFNAR-signaling on the level of CD8 1 T cells was associated with reduced expansion of gp33-specific T cells upon infection with lymphocytic choriomeningitis virus (LCMV). This phenomenon was less pronounced upon infection with VACV gp33 [12]. Interestingly, instead of enhancing T-cell function, IFN can also lead to T-cell attrition or activation induced cell death [13,14].To further study the impact of virus-induced IFN on the stimulation of virus-specific T-cell responses, we analyzed expansion of antigen-specific T cells upon infection with two closely related viruses, vaccinia virus (VACV) and modified vaccinia virus Ankara (MVA), which upon infection either suppress or induce IFN responses, respectively. VACV d...

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supporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

et al. 2010

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“…These findings indicate that induction of diabetogenic T cell responses are different in pCI/ppins-and pCI/pins-immunized RIP-B7.1 mice, and they confirm previous findings reported for the NOD mouse system (33). Thus, immunization of RIP-B7.1 mice with the pCI/pins vector may lead to EAD by inducing CD8 T cell responses that have specificities other than K b /A [12][13][14][15][16][17][18][19][20][21] . In support of this hypothesis, we showed that a mutant ppins with a deletion of the A 12-21 sequence (pCI/ppins⌬ A12-21 ) induced CD8 T cellmediated EAD in RIP-B7.1 mice (Fig.…”

Section: Expression Of Ppins In the Ersupporting

confidence: 89%

“…Most of these peptides are derived from proteins through degradation by proteasomes and are delivered to newly synthesized, ER-resident class I molecules by TAP (19). It is assumed that proteasomes generate the COOH termini of MHC class I-binding peptides and that ER-associated aminopeptidases trim off NH 2 -terminal extensions (20,21). Direct ER-associated Ag processing and subsequent MHC class I-loading of antigenic peptides has been described (10,(22)(23)(24)(25)(26).…”

Section: T Ype 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

“…This streamlined processing may increase the presentation efficacy of these epitopes (23,27). Skowera et al identified two HLA-A*0201-restricted epitopes that were localized at the extreme COOH terminus of the 24 residue human ppins SP (i.e., ppins [15][16][17][18][19][20][21][22][23][24] and ppins [17][18][19][20][21][22][23][24] ) (10). CD8 T cells with these specificities were found in patients with T1D, suggesting that they may be directly involved in this disease (10 …”

Section: T Ype 1 Diabetes Mellitus (T1d)mentioning

confidence: 99%

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Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses

Brosi

Reiser

Rajasalu

et al. 2009

The Journal of Immunology

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RIP-B7.1 mice express the costimulator molecule B7.1 (CD80) on pancreatic β cells and are a well-established model for studying de novo induction of diabetogenic CD8 T cells. Immunization of RIP-B7.1 mice with preproinsulin (ppins)-encoding plasmid DNA efficiently induces experimental autoimmune diabetes (EAD). EAD is associated with an influx of CD8 T cells specific for the Kb/A12–21 epitope into the pancreatic islets and the subsequent destruction of β cells. In this study, we used this model to investigate how ppins-derived Ags are expressed and processed to prime diabetogenic, Kb/A12–21-specific CD8 T cells. Targeting the Kb/A12–21 epitope, the insulin A chain, or the ppins to the endoplasmic reticulum (ER) (but not to the cytosol and/or nucleus) efficiently elicited Kb/A12–21-specific CD8 T cell responses. The Kb/A12–21 epitope represents the COOH terminus of the ppins molecule and, hence, did not require COOH-terminal processing before binding its restriction element in the ER. However, Kb/A12–21-specific CD8 T cells were also induced by COOH-terminally extended ppins-specific polypeptides expressed in the ER, indicating that the epitope position at the COOH terminus is less important for its diabetogenicity than is targeting the Ag to the ER. The Kb/A12–21 epitope had a low avidity for Kb molecules. When epitopes of unrelated Ags were coprimed at the same site of Ag delivery, “strong” Kb-restricted (but not Db-restricted) CD8 T cell responses led to the suppression of Kb/A12–21-specific CD8 T cell priming and reduced EAD. Thus, direct expression and processing of the “weak” Kb/A12–21 epitope in the ER favor priming of autoreactive CD8 T cells.

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Immunology of the Fetus

Wedgwood

McNamara

2007

Clinical Obstetrics

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The Ins and Outs of Intracellular Peptides and Antigen Presentation by MHC Class I Molecules

Cited by 16 publications

References 80 publications

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

Concomitant type I IFN receptor‐triggering of T cells and of DC is required to promote maximal modified vaccinia virus Ankara‐induced T‐cell expansion

Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses

Immunology of the Fetus

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