Polyfunctional Cytomegalovirus-Specific CD4+ and pp65 CD8+ T Cells Protect Against High-Level Replication After Liver Transplantation

Nebbia, Gaia; Mattes, Frank; Smith, Colette; Hainsworth, Emma; Kopycinski, Jakub; Burroughs, Andrew K.; Griffiths, PD; Klenerman, Paul; Emery, Vincent C.

doi:10.1111/j.1600-6143.2008.02425.x

Cited by 86 publications

(63 citation statements)

References 39 publications

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“…43,44 This may be related to the fact that polyfunctional T-cells produce higher levels of cytokines per cell, 45 but we suggest that the picture is more complex. To review the relationship between the functional subsets, we employed hierarchical clustering of the functional subtypes across seropositive individuals.…”

Section: Discussionmentioning

confidence: 92%

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Krol

Stuchlý

Hubáček

et al. 2010

Bone Marrow Transplant

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Depletion of cellular immunity as a consequence of conditioning before allogeneic hematopoietic SCT (HSCT) frequently results in CMV reactivation, which may in turn lead to life-threatening infections and require timely antiviral treatment. We have investigated the functional signatures of CMV-specific CD4 þ and CD8 þ T-cells in 191 samples from 118 individuals. We compared healthy donors with both patients with high and undetectable viral loads, and those who controlled and did not control their CMV reactivations. Polychromatic flowcytometric measurements of CD154 (CD40L), intracellular cytokines (IFNc, IL2) and a degranulation marker (CD107a) allowed us to assess the functional status of various T-cells simultaneously. We found that dual IFNc/ IL2-producing CD8 þ T-cells were present in patients controlling their CMV reactivations but absent from noncontrollers. CD8 þ T-cells that produce only IFNc were the most abundant subtype, but they most likely represent non-protective memory cells. Distinct functional signatures were examined by hierarchical clustering, and this revealed that, unlike polyfunctional CD8 þ T-cells, CD8 þ T-cells that produce IFNc alone were not functioning in concert with other subsets. In conclusion, our study revealed functional signatures that may be useful for immune monitoring, and it could change the interpretation of previous studies that assessed only IFNc.

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Section: Discussionmentioning

confidence: 92%

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Krol

Stuchlý

Hubáček

et al. 2010

Bone Marrow Transplant

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“…Our data therefore reveal an important new role for vaccine-induced IL-2-secreting memory T cells and may, in part, explain the emerging consensus that polyfunctional T cells, which secrete IL-2 in addition to IFN-g or TNF-a, are associated with positive outcomes of viral infection (30)(31)(32) and with particularly effective vaccination regimes (33,34).…”

Section: Discussionmentioning

confidence: 95%

NK Cells as Effectors of Acquired Immune Responses: Effector CD4+ T Cell-Dependent Activation of NK Cells Following Vaccination

Horowitz

Behrens

Okell

et al. 2010

The Journal of Immunology

153

158

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We characterized vaccine-induced cellular responses to rabies virus in naive adult volunteers. Contrary to current paradigms, we observed potent and prolonged in vitro NK cell cytokine production and degranulation responses after restimulation of PBMCs with inactivated rabies virus in vaccinated, but not in unvaccinated, individuals. This “recall” NK cell response was absolutely dependent on Ag-specific IL-2 from CD45RO+ CD4+ T cells as well as IL-12 and IL-18 from accessory cells. Importantly, NK cells represented over 70% of all IFN-γ–secreting and degranulating cells in the first 12–18 h after virus rechallenge indicating they may be required for rapid control of infection after vaccination. Activation of NK cells may be a critical function of IL-2–secreting effector memory T cells. Although IL-2–dependent postvaccination NK cell activation has been reported previously, this is the first time the magnitude of this effect and its contribution to the overall vaccine-induced response has been appreciated and the mechanisms of NK activation postvaccination have been elucidated. Our data will allow standard protocols for evaluating vaccine-induced immunity to be adapted to assess NK cell effector responses.

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“…Both IFN-g À IL-2 1 central memory T cells as well as the so-called multifunctional CD8 1 and CD4 1 T cells simultaneously producing IFN-g, TNF and IL-2 were shown to mediate long-term immunity to Leishmania in mice [35,36]. Recent reports, as reviewed by Makedonas and Betts [37], suggest that multifunctional CD8 1 memory T cells are crucial for disease control in HIV infection [38,39] and polyfunctional CMV-specific CD4 1 and pp65 CD8 1 T cells protect against highlevel replication after liver transplantation [40].Several studies brought new insights into complexity of the CD4 1 [41] and CD8 1 [42,43] T-cell memory, but data on the more detailed analysis of memory T-cell response to EBV are missing.In this study we performed a multiparameter flow cytometry approach to comprehensively analyze the EBV-specific T-cell response in latent infection. Using 15-mer overlapping proteinspanning peptide pools of latent EBNA-1 and lytic BZLF-1 we characterized EBV-specific memory CD4 1 and CD8 1 T cells based on cytokine-producing capability (IL-2, TNF, IFN-g), and differentiation marker expression (CCR7, CD45RA).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Guerreiro

Letsch

et al. 2010

Eur J Immunol

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EBV infection leads to life-long viral persistence. Although EBV infection can result in chronic disease and malignant transformation, most carriers remain disease-free as a result of effective control by T cells. EBV-specific IFN-c-producing T cells could be demonstrated in acute and chronic infection as well as during latency. Recent studies, however, provide evidence that assessing IFN-c alone is insufficient to assess the quantity and quality of a T-cell response. Using overlapping peptide pools of latent EBV nuclear antigen 1 and lytic BZLF-1 protein and multicolor flow cytometry, we demonstrate that the majority of ex vivo EBV-reactive T cells in healthy virus carriers are indeed IL-2-and/or TNF-producing memory cells, the latter being significantly more frequent in BM. After in vitro expansion, a substantial number of EBV-specific CD4 1 and CD8 1 T cells retained a CC-chemokine receptor 7 (CCR7)-positive memory phenotype. Based on their cytokine profiles, six different EBV-specific T-cell subsets could be distinguished with TNF-single or TNF/IL-2-double producing cells expressing the highest CCR7 levels resembling earlydifferentiated memory T cells. Our study delineates the memory T-cell profile of a protective immune response and provides a basis for analyzing T-cell responses in EBVassociated diseases.Key words: BM . EBV . Immune monitoring . Multifunctional T cells . T-cell memory IntroductionEBV is a human gamma herpesvirus that is widespread in all human populations. Following oral transmission, EBV replicates in the oropharyngeal epithelial cells and infects mucosal B cells, leading to a life-long persistence in the memory B-cell pool [1,2]. The primary infection occurs usually during childhood and is often asymptomatic; however, infection is manifested as acute infectious mononucleosis in a subset of patients [3]. Despite the relatively benign course in most carriers, EBV reactivation is considered as a risk-factor both for malignant transformation and autoimmune diseases. The ability of the EBV encoded protein 1566LMP-1 to induce T-cell-independent immunoglobulin class switch DNA recombination and BAFF, a B-cell activating factor, that rescues self-reactive T cells, is considered to play an important role in the pathogenesis of EBV-related autoimmune and lymphoproliferative disease [4]. EBV is causatively linked to nasopharyngeal carcinoma and B-cell malignant diseases such as endemic Burkitt's lymphoma, Hodgkin's lymphoma and posttransplant lymphoproliferative diseases (PTLD) [5][6][7]. Recent data suggest that EBV is associated with various autoimmune diseases as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and primary Sjögren's syndrome [8,9]. Chronic active EBV infection can also cause Chronic Fatigue Syndrome, which is frequently associated with autoimmune thyreoiditis [10].The EBV cycle has two distinct stages, the latent infection where the genome is maintained at a constant copy number per cell and limited regions of the genome are expressed and the lytic cycle w...

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Polyfunctional Cytomegalovirus-Specific CD4+ and pp65 CD8+ T Cells Protect Against High-Level Replication After Liver Transplantation

Abstract: To determine whether polyfunctional CD4+ T-cell responses coupled with CD8+ T-cell responses against

Cited by 86 publications

References 39 publications

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

Signature profiles of CMV-specific T-cells in patients with CMV reactivation after hematopoietic SCT

NK Cells as Effectors of Acquired Immune Responses: Effector CD4+ T Cell-Dependent Activation of NK Cells Following Vaccination

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

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