Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8<sup>+</sup>T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons

Almanzar, Giovanni; Schwaiger, Susanne; Jenewein, Brigitte; Keller, Michael; Herndler‐Brandstetter, Dietmar; Würzner, Reinhard; Schönitzer, Diether; Grubeck‐Loebenstein, Beatrix

doi:10.1128/jvi.79.6.3675-3683.2005

Cited by 321 publications

(300 citation statements)

References 41 publications

Supporting

Mentioning

272

Contrasting

Unclassified

Order By: Relevance

“…Although the TCR usage of these responses was not studied, we envisage considerable focusing because CMV-specific CD8 T cells are usually manifest as massive clonal expansions (17). Combined with other studies (43)(44)(45) this has led to a revised view of the consequences of long-term CMV carriage for the immunocompetent host.…”

Section: Discussionmentioning

confidence: 99%

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

Khan

Best

Bruton

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Replication of human cytomegalovirus is controlled by a vigorous CD8 T cell response. The persistent nature of infection is believed to periodically stimulate T cell responses resulting in considerable expansions of virus-specific CD8 T cells over time. In this study, we describe the magnitude and breadth of CD8 T cell responses against the immunodominant viral Ags, IE-1 and pp65, in acute and long-term infection using the IFN-γ ELISPOT assay. Simultaneously, we have identified several novel MHC class I restricted CD8 T cell epitopes. Acute phase responses in immunocompetent donors appear to be extremely focused as early as 1 week post diagnosis with dominant peptide-specific responses observed against both proteins. These dominant responses remain detectable at all later time points over a 4-year follow-up. Interestingly the IE-1 responses show an increase over time whereas the pp65 responses do not, which contrasts with data showing that responses against both Ags are elevated in elderly individuals. We also observe the rapid emergence of an effector memory phenotype for virus-specific CD8 T cells as observed in persistent infection. Over time the revertant CD45RApos effector cell population is also expanded, and this is more evident in the preferentially expanded IE-1 responses. We postulate that periodic low-level virus reactivation after the acute infection phase preferentially stimulates these responses whereas pp65-specific T cell expansions probably occur during the infrequent episodes of lytic viral replication or secondary infection.

show abstract

Section: Discussionmentioning

confidence: 99%

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

Khan

Best

Bruton

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Ϫ effector cell accumulation and in young individuals, who characteristically have high numbers of naive CD8 ϩ T cells and low memory/effector counts (15).…”

Section: Cd25mentioning

confidence: 99%

“…1B). CD25 mRNA analysis was performed using PCR and CD25-specific primers (15). Surface phenotype analysis of CD25 ϩ and CD25 Ϫ CD8 ϩ T cells by four-color flow cytometric analysis additionally revealed that both subpopulations were Ag-experienced T cells, because they expressed CD45RO, CD44 high , and CD95 (Fig.…”

Section: Cd8mentioning

confidence: 99%

“…CMV-specific CD8 ϩ T cells have also been shown to occur as large expanded clones that may dominate the repertoire (14). In a recent publication (15), we demonstrated that aging as well as CMV infection lead to a decrease in the size of the naive CD8 ϩ T cell pool, but to an increase in the number of IFN-␥-producing CD8 ϩ CD28 Ϫ effector T cells. The size of the CD8 ϩ memory T cell population that produces IL-2 and IL-4 also increases with aging, but this increase is missing in CMV carriers.…”

mentioning

confidence: 99%

See 1 more Smart Citation

CD25-Expressing CD8+ T Cells Are Potent Memory Cells in Old Age

Herndler‐Brandstetter¹,

Schwaiger²,

Veel³

et al. 2005

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

We have recently described an IL-2/IL-4-producing CD8+CD25+ nonregulatory memory T cell population that occurs in a subgroup of healthy elderly persons who characteristically still have a good humoral response after vaccination. The present study addresses this specific T cell subset and investigates its origin, clonal composition, Ag specificity, and replicative history. We demonstrate that CD8+CD25+ memory T cells frequently exhibit a CD4+CD8+ double-positive phenotype. The expression of the CD8 αβ molecule and the occurrence of signal-joint TCR rearrangement excision circles suggest a thymic origin of these cells. They also have longer telomeres than their CD8+CD25− memory counterparts, thus indicating a shorter replicative history. CD8+CD25+ memory T cells display a polyclonal TCR repertoire and respond to IL-2 as well as to a panel of different Ags, whereas the CD8+CD25− memory T cell population has a more restricted TCR diversity, responds to fewer Ags, and does not proliferate in response to stimulation with IL-2. Molecular tracking of specific clones with clonotypic primers reveals that the same clones occur in CD8+CD25+ and CD8+CD25− memory T cell populations, demonstrating a lineage relationship between CD25+ and CD25− memory CD8+ T cells. Our results suggest that CD25-expressing memory T cells represent an early stage in the differentiation of CD8+ cells. Accumulation of these cells in elderly persons appears to be a prerequisite of intact immune responsiveness in the absence of naive T cells in old age.

show abstract

“…112 In the elderly, such CMVspecific T cells can comprise up to 15% of the total blood T-cell population. 113 We demonstrated that patients who are seropositive for CMV and who have CLL have increased relative and absolute numbers of CD8 ϩ T cells with this phenotype relative to that of age-matched control subjects. 114 This was independent of any evidence for active viremia.…”

Section: Improving T-cell Function and Activationmentioning

confidence: 99%

Cellular immune therapy for chronic lymphocytic leukemia

Kater

Oers

Kipps

2007

Blood

View full text Add to dashboard Cite

Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for chemotherapyresistant leukemia-cell subclones. Cellular immune therapy promises to mitigate these complications and potentially provide for curative treatment. Most experience with this is in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), in which graft-versus-leukemia (GVL) effects can be observed and shown responsible for long-term disease-free survival. However, use of allo-HSCT for CLL is limited because of the lack of suitable donors and the treatment-related morbidity/mortality for elderly patients, who constitute the majority at risk for developing this disease. The GVL effect, however, suggests there are specific CLL-associated antigens that could be targeted in autologous cellular immune therapy. Effective strategies for this will have to overcome the disease-related acquired immune deficiency and the capacity of the leukemia-cell to induce T-cell tolerance, thereby compromising the activity of even conventional vaccines in patients with this disease. We will discuss the different strategies being developed to overcome these limitations that might provide for effective cellular immune therapy of CLL. IntroductionChronic lymphocytic leukemia (CLL) is a CD5 ϩ B-cell malignancy that is considered incurable. Historically, the first-line treatment consisted of alkylating agents, which resulted in response rates in up to 70% of patients, but did not improve survival. 1 Treatment regimens with the nucleoside (purine) analogs, such as fludarabine monophosphate (F-ara-A) or pentostatin, were found to yield higher response rates and to provide for longer progression-free survival, 2 especially in combination with cyclophosphamide. 3 However, despite effecting increased complete response rates, treatment with purine analogs alone does not appear to improve survival. 2 Newer treatment combinations have incorporated use of monoclonal antibodies to chemotherapy. 4,5 Although treatment with such combinations might provide for a first-time-observed survival benefit, 6 such therapy still is not considered curative.Although most patients initially respond to these chemotherapeutic approaches, many develop therapy-resistant disease with repeated therapy. Patients with refractory disease more frequently have leukemia cells that harbor deletions in the short arm of chromosome 17 (17pϪ), which often is associated with loss of functional p53, or in the long arm of chromosome 11 (11qϪ) in and/or around the gene encoding the ataxia telangectasia (ATM), which is a kinase required for p53 function. 7,8 Moreover, many chemotherapy-refractory patients have leukemia cells that have lost functional p53. Because the cytoreductive activity of most chemotherapy agents requires functional p53, 9,10 loss of p53 is ...

show abstract

Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8⁺T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons

Cited by 321 publications

References 41 publications

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

CD25-Expressing CD8+ T Cells Are Potent Memory Cells in Old Age

Cellular immune therapy for chronic lymphocytic leukemia

Contact Info

Product

Resources

About

Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8+T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons

Cited by 321 publications

References 41 publications

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

T Cell Recognition Patterns of Immunodominant Cytomegalovirus Antigens in Primary and Persistent Infection

CD25-Expressing CD8+ T Cells Are Potent Memory Cells in Old Age

Cellular immune therapy for chronic lymphocytic leukemia

Contact Info

Product

Resources

About

Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8⁺T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons