Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8<sup>+</sup>T Lymphocytes in Healthy Seropositive Donors

Gillespie, Geraldine M.; Wills, Mark R.; Appay, Victor; O’Callaghan, Chris; Murphy, Mike; Smith, Nerida Ann; Sissons, Patrick; Rowland‐Jones, Sarah; Bell, John I.; Moss, Paul

doi:10.1128/jvi.74.17.8140-8150.2000

Cited by 397 publications

(316 citation statements)

References 50 publications

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“…Using 15-mer peptide pools, both CD4 + and CD8 + IFN-c-producing T cell responses can be elicited, as with 8-12-mer mixes [12]. HCMVspecific CD8 + T cell frequency of healthy subjects determined by the method herein reported is similar to those previously reported for IE-or pp65-specific CD8 + T cells [12,16]. Although pp65 and IE proteins are currently considered the predominant viral stimuli of the HCMV-specific cell-mediated immune response, other viral proteins are involved in this process [17].…”

Section: Discussionsupporting

confidence: 81%

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

et al. 2005

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Immature dendritic cells (DC) infected with an endotheliotropic (Huv + ) and leukotropic (Leuk + ) human cytomegalovirus (HCMV) strain were used as a stimulus to determine functional HCMV-specific CD4 + and CD8 + T cells. Infected DC were cocultured with autologous peripheral blood mononuclear cells and both arms of T cell activation were determined by intracellular flow cytometry analysis of IFN-c production. Efficient stimulation of HCMV-specific CD4 + and CD8 + T cell responses was achieved using DC productively infected with Huv + Leuk + VR1814 strain. On the contrary, a negligible CD8 + T cell response was obtained when HCMV strains unable to infect DC, or DC pulsed with inactivated viral antigen, were used. HCMV specificity of the T cell response was confirmed in 46 HCMV-seropositive and 8 HCMV-seronegative healthy subjects. A cut-off was established to discriminate between immune and nonimmune subjects. The novel ex vivo assay enables the simultaneous evaluation of HCMV-specific CD4 + and CD8 + T cell responses and may be a useful tool for monitoring HCMV-specific T cell activity in immunocompromised transplanted patients.

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Section: Discussionsupporting

confidence: 81%

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

et al. 2005

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“…These results strongly suggest that the majority of HCMV-specific memory CD8 ϩ T cells have a CCR5 ϩ CCR7 Ϫ phenotype. Because most HCMV-specific CD8 ϩ T cells are CD28 Ϫ CD45RA Ϫ CD8 ϩ and CD28 Ϫ CD45RA ϩ CD8 ϩ T cells, these findings together support the idea that HCMV-specific CD8 ϩ T cells are well-differentiated CD8 ϩ T cells (32).…”

Section: Figuresupporting

confidence: 66%

Functional Expression of the Chemokine Receptor CCR5 on Virus Epitope-Specific Memory and Effector CD8+ T Cells

Fukada

Sobao

Tomiyama

et al. 2002

The Journal of Immunology

109

117

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Because the chemokine receptor CCR5 is expressed on Th1 CD4+ cells, it is important to investigate the expression and function of this receptor on other T cells involved in Th1 immune responses, such as Ag-specific CD8+ T cells, which to date have been only partially characterized. Therefore, we analyzed the expression and function of CCR5 on virus-specific CD8+ T cells identified by HLA class I tetramers. Multicolor flow cytometry analysis demonstrated that CCR5 is expressed on memory (CD28+CD45RA−) and effector (CD28−CD45RA− and CD28−CD45RA+) CD8+ T cells but not on naive (CD28+CD45RA+) CD8+ T cells. CCR5 expression was much lower on two effector CD8+ T cells than on memory CD8+ T cells. Analysis of CCR7 and CCR5 expression on the different types of CD8+ T cells showed that memory CD8+ T cells have three phenotypic subsets, CCR5+CCR7−, CCR5+CCR7+, and CCR5−CCR7+, while naive and effector CD8+ T cells have CCR5−CCR7+ and CCR5+CCR7− phenotypes, respectively. These results suggest the following sequence for differentiation of memory CD8+ T cells: CCR5−CCR7+→CCR5+CCR7+→CCR5+CCR7−. CCR5+CD8+ T cells effectively migrated in response to RANTES, suggesting that CCR5 plays a critical role in the migration of Ag-specific effector and differentiated memory CD8+ T cells to inflammatory tissues and secondary lymphoid tissues. This is in contrast to CCR7, which functions as a homing receptor in migration of naive and memory CD8+ T cells to secondary lymphoid tissues.

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“…This pattern is consistent with the dominant CD27 ϩ CD45RA Ϫ CCR7 Ϫ phenotype of HIV-specific CD8 ϩ T cells observed in adults (35,47). It is also similar to the less biased, but still largely CD45RO ϩ CD45RA Ϫ CD27 ϩ phenotype of circulating CD8 ϩ T cells specific for Epstein-Barr virus (48,49), influenza virus (50), and CMV in HIVnegative individuals, although it should be stressed that, in particular, the CMV-specific cells display more diverse phenotypes in healthy subjects (30,50,51).…”

Section: Discussionmentioning

confidence: 72%

HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment

Sandberg

Fast

Jordan

et al. 2003

The Journal of Immunology

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The immunology of vertical HIV transmission differs from that of adult infection in that the immune system of the infant is not fully matured, and the factors that influence the functionality of CD8+ T cell responses against HIV in children remain largely undefined. We have investigated CD8+ T cell responses in 65 pediatric subjects with vertically acquired HIV-1 infection. Vigorous, broad, and Ag dose-driven CD8+ T cell responses against HIV Ags were frequently observed in children who were older than 3 years of age and maintained CD4+ T cell counts >400 cells/μl. In contrast, younger age or a CD4+ T cell count <400 cells/μl was associated with poor CD8+ T cell responses and high HIV loads. Furthermore, subjects with a severely depleted and phenotypically altered CD4+ T cell compartment had circulating Gag-specific CD8+ T cells with impaired IFN-γ production. When viral load was not suppressed by antiviral treatment, subjects that fell below the putative age and CD4+ T cell count thresholds had significantly reduced CD8+ T cell responses and significantly higher viral loads. Thus, the data suggest that fully effective HIV-specific CD8+ T cell responses take years to develop despite an abundance of Ag in early life, and responses are further severely impaired, independent of age, in children who have a depleted or skewed CD4+ T cell compartment. The results are discussed in relation to differences between the neonatal and adult immune systems in the ability to respond to HIV infection.

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Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8⁺T Lymphocytes in Healthy Seropositive Donors

Cited by 397 publications

References 50 publications

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

Functional Expression of the Chemokine Receptor CCR5 on Virus Epitope-Specific Memory and Effector CD8+ T Cells

HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment

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Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8+T Lymphocytes in Healthy Seropositive Donors

Cited by 397 publications

References 50 publications

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

Simultaneous quantification of human cytomegalovirus (HCMV)-specific CD4+ and CD8+T cells by a novel method using monocyte-derived HCMV-infected immature dendritic cells

Functional Expression of the Chemokine Receptor CCR5 on Virus Epitope-Specific Memory and Effector CD8+ T Cells

HIV-Specific CD8+ T Cell Function in Children with Vertically Acquired HIV-1 Infection Is Critically Influenced by Age and the State of the CD4+ T Cell Compartment

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Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8⁺T Lymphocytes in Healthy Seropositive Donors