Human CD4+ T Cells Displaying Viral Epitopes Elicit a Functional Virus-Specific Memory CD8+ T Cell Response

Adamopoulou, Eleni; Diekmann, Jan; Kuntz, Gaby; Einsele, Hermann; Rammensee, Hans‐Georg; Topp, Max S.

doi:10.4049/jimmunol.178.9.5465

Cited by 23 publications

(25 citation statements)

References 38 publications

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“…Indeed, the presence of natural or vaccine-induced HSV-specific antibodies has shown no appreciable effect on infection and reactivation [94], [97]–[101] in humans. Although other groups have demonstrated that the presence of HSV antibodies correlates with protection in animal model [98].…”

Section: Discussionmentioning

confidence: 99%

An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

et al. 2014

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Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are common infectious agents in both industrialized and developing countries. They cause recurrent asymptomatic and/or symptomatic infections, and life-threatening diseases and death in newborns and immunocompromised patients. Current treatment for HSV relies on antiviral medications, which can halt the symptomatic diseases but cannot prevent the shedding that occurs in asymptomatic patients or, consequently, the spread of the viruses. Therefore, prevention rather than treatment of HSV infections has long been an area of intense research, but thus far effective anti-HSV vaccines still remain elusive. One of the key hurdles to overcome in anti-HSV vaccine development is the identification and effective use of strategies that promote the emergence of Th1-type immune responses against a wide range of epitopes involved in the control of viral replication. Since the HIV1 Tat protein has several immunomodulatory activities and increases CTL recognition of dominant and subdominant epitopes of heterologous antigens, we generated and assayed a recombinant attenuated replication-competent HSV1 vector containing the tat gene (HSV1-Tat). In this proof-of-concept study we show that immunization with this vector conferred protection in 100% of mice challenged intravaginally with a lethal dose of wild-type HSV1. We demonstrate that the presence of Tat within the recombinant virus increased and broadened Th1-like and CTL responses against HSV-derived T-cell epitopes and elicited in most immunized mice detectable IgG responses. In sharp contrast, a similarly attenuated HSV1 recombinant vector without Tat (HSV1-LacZ), induced low and different T cell responses, no measurable antibody responses and did not protect mice against the wild-type HSV1 challenge. These findings strongly suggest that recombinant HSV1 vectors expressing Tat merit further investigation for their potential to prevent and/or contain HSV1 infection and dissemination.

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Section: Discussionmentioning

confidence: 99%

An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

et al. 2014

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“…Specific clones were generated by limiting dilution cloning in 96-well plates. Surface and tetramer stainings were performed, as previously reported (20), using HLA-A02 tetramers complexed with the peptide YLL, YLQ, or CLG all PE labeled (Proimmune), together with a FITClabeled anti-CD8 and a PerCP-labeled anti-CD3 Ab (BD Biosciences). Samples were analyzed using a FACSCalibur flow cytometer and the CellQuest Pro software (BD Biosciences).…”

Section: Generation Of Epitope-specific Cd8 ϩ T Cells and Cd8 ϩ T Celmentioning

confidence: 99%

Processing of Two Latent Membrane Protein 1 MHC Class I Epitopes Requires Tripeptidyl Peptidase II Involvement

Diekmann

Adamopoulou

Beck

et al. 2009

The Journal of Immunology

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The EBV Ag latent membrane protein 1 (LMP1) has been described as a potential target for T cell immunotherapy in EBV-related malignancies. However, only a few CD8+ T cell epitopes are known, and the benefit of LMP1-specific T cell immunotherapy has not yet been proven. In this work, we studied the processing of the two LMP1 HLA-A02-restricted epitopes, YLLEMLRWL and YLQQNWWTL. We found that target cells endogenously expressing the native LMP1 are not recognized by CTLs specific for these epitopes because the N-terminal part of LMP1 limits the efficiency of epitope generation. We further observed that the proteasome is not required for the generation of both epitopes and that the YLLEMLRWL epitope seems to be destroyed by the proteasome, because blocking of proteasomal activities enhanced specific CTL activation. Activation of LMP1-specific CTLs could be significantly reduced after inhibition of the tripeptidyl peptidase II, suggesting a role for this peptidase in the processing of both epitopes. Taken together, our results demonstrate that the MHC class I-restricted LMP1 epitopes studied in this work are two of very few epitopes known to date to be processed proteasome independently by tripeptidyl peptidase II.

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“…For example, Brandes et al (5) demonstrated that human ␥␦ T cells expressing MHC class II and costimulatory molecules can stimulate naive ␣␤ T cell proliferation and differentiation. Kennedy et al (6) reported that the active Th lymphocytes when pulsed with Ag peptides can cross-prime memory CTL responses, whereas Adamopoulou et al (7) showed that human CD4 ϩ T cells displaying viral epitopes elicited a functional virus-specific memory CD8 ϩ T cell response.…”

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confidence: 99%

CD4+ Th-APC with Acquired Peptide/MHC Class I and II Complexes Stimulate Type 1 Helper CD4+ and Central Memory CD8+ T Cell Responses

Umeshappa

Huang

Xie

et al. 2009

The Journal of Immunology

104

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T cell-T cell Ag presentation is increasingly attracting attention. We previously showed that the in vitro OVA-pulsed dendritic cell (DCOVA)-activated CD4+ Th cells acquired OVA peptide/MHC (pMHC) class I and costimulatory molecules such as CD54 and CD80 from DCOVA and acted as CD4+ Th-APC capable of stimulating OVA-specific CD8+ CTL responses. In this study, we further applied the OVA-specific TCR-transgenic OT I and OT II mice with deficiency of various cytokines or costimulatory molecule genes useful for studying the molecular mechanisms underlying in Th-APC’s stimulatory effect. We demonstrated that DCOVA-stimulated OT II CD4+ Th-APC also acquired costimulatory molecules such as CD40, OX40L, and 4-1BBL and the functional pMHC II complexes by DCOVA activation. CD4+ Th-APC with acquired pMHC II and I were capable of stimulating CD4+ Th1 and central memory CD8+44+CD62LhighIL-7R+ T cell responses leading to antitumor immunity against OVA-expressing mouse B16 melanoma. Their stimulatory effect on CD8+ CTL responses and antitumor immunity is mediated by IL-2 secretion, CD40L, and CD80 signaling and is specifically targeted to CD8+ T cells in vivo via acquired pMHC I. In addition, CD4+ Th-APC expressing OVA-specific TCR, FasL, and perforin were able to kill DCOVA and neighboring Th-APC expressing endogenous and acquired pMHC II. Taken together, we show that CD4+ Th-APC can modulate immune responses by stimulating CD4+ Th1 and central memory CD8+ T cell responses and eliminating DCOVA and neighboring Th-APC. Therefore, our findings may have great impacts in not only the antitumor immunity, but also the regulatory T cell-dependent immune tolerance in vivo.

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Human CD4+ T Cells Displaying Viral Epitopes Elicit a Functional Virus-Specific Memory CD8+ T Cell Response

Cited by 23 publications

References 38 publications

An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

An Attenuated Herpes Simplex Virus Type 1 (HSV1) Encoding the HIV-1 Tat Protein Protects Mice from a Deadly Mucosal HSV1 Challenge

Processing of Two Latent Membrane Protein 1 MHC Class I Epitopes Requires Tripeptidyl Peptidase II Involvement

CD4+ Th-APC with Acquired Peptide/MHC Class I and II Complexes Stimulate Type 1 Helper CD4+ and Central Memory CD8+ T Cell Responses

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