Cytomegalovirus infection modulates the phenotype and functional profile of the T-cell immune response to mycobacterial antigens in older life

Infection with Cytomegalovirus is associated with accelerated immunosenescence. Expansions of CMV-specific T cell responses have previously been demonstrated to affect the ability of T cells to respond to other infections. Most people above 60 years of age display M. tuberculosis-specific immunity because of vaccination, exposure, or both. T-cell responses can be assessed by measuring intracellular IFN-γ in vitro after tuberculin stimulation. Here we investigated tuberculin-specific CD4 T-cell responses in independently living healthy older people in the South of England using flow-cytometry. Individuals were investigated for tuberculin and CMV-specific T-cell immunity using in vitro antigen stimulation followed by intracellular staining for IFN-γ, TNF-α, IL2, as well as degranulation and CD154 upregulation. We also examined a control group of younger individuals (20–35 years of age). There was no significant difference between older and young people in regards to tuberculin responsiveness of CD4 T-cells; however, older people seemed to show more outliers. Increased responsiveness to tuberculin was significantly correlated to CMV responsiveness but not age. In older donors, the memory phenotype of tuberculin-induced T-cells was significantly skewed towards a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals and the degree of skewing correlated quantitatively with the size of the CMV-specific CD4 T-cell response. This is a fundamental advance over previous reports of changes of the tuberculin-specific CD4 T-cell response with CMV serostatus. Our results show that how the immune system responds to CMV has a fundamental impact on the phenotype and function of the immune response to mycobacterial antigens in older life

Functional diversity of CMV-specific T-cells is maintained in older people and significantly associated with protein specificity and response size

Background: Parallel up-regulation of several T-cell effector functions (‘polyfunctionality’) is believed to be critical for the protection against viruses but thought to decrease in large T-cell expansions, in particular at older ages. The factors determining T-cell polyfunctionality are incompletely understood. Here we revisit the question of CMV-specific T-cell polyfunctionality, including a wide range of T-cell target proteins, response sizes, and participant ages. Methods: Polychromatic flow-cytometry was used to analyze the functional diversity (CD107, CD154, IL-2, TNF, IFN-) of CD4 and CD8 T-cell responses to 19 CMV proteins in a large group of young and older UK participants. A group of oldest old people (>85years) was included to explore these parameters in exceptional ‘survivors’. Polyfunctionality was assessed for each proteinspecific response subset by subset and in aggregate across all proteins using the novel polyfunctionality index (PI). Results: Polyfunctionality was not reduced in healthy older compared to young people. However, it was significantly related to target protein specificity. For each protein it increased with response size. In the oldest old overall T-cell polyfunctionality was significantly lower. Discussion: Our results give a new perspective on T-cell polyfunctionality and raise the question if maintaining polyfunctionality of CMV-specific T-cells at older ages is necessarily beneficial

Bovine pestivirus is a new alternative virus for multiple myeloma oncolytic virotherapy

The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients' antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46

Report from the second cytomegalovirus and immunosenescence workshop.

The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vaccination. This commentary summarizes the major findings of these presentations and references subsequently published work from the presenter laboratory where appropriate and draws together major themes that were subsequently discussed along with new areas of interest that were highlighted by this discussion.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Cytomegalovirus infection modulates the phenotype and functional profile of the T-cell immune response to mycobacterial antigens in older life

Infection with Cytomegalovirus is associated with accelerated immunosenescence. Expansions of CMV-specific T cell responses have previously been demonstrated to affect the ability of T cells to respond to other infections. Most people above 60years of age display M. tuberculosis-specific immunity because of vaccination, exposure, or both. T-cell responses can be assessed by measuring intracellular IFN-γ in vitro after tuberculin stimulation. Here we investigated tuberculin-specific CD4 T-cell responses in independently living healthy older people in the South of England using flow-cytometry. Individuals were investigated for tuberculin and CMV-specific T-cell immunity using in vitro antigen stimulation followed by intracellular staining for IFN-γ, TNF-α, IL2, as well as degranulation and CD154 upregulation. We also examined a control group of younger individuals (20-35years of age). There was no significant difference between older and young people in regards to tuberculin responsiveness of CD4 T-cells; however, older people seemed to show more outliers. Increased responsiveness to tuberculin was significantly correlated to CMV responsiveness but not age. In older donors, the memory phenotype of tuberculin-induced T-cells was significantly skewed towards a more terminal differentiation phenotype in CMV-infected compared to uninfected individuals and the degree of skewing correlated quantitatively with the size of the CMV-specific CD4 T-cell response. This is a fundamental advance over previous reports of changes of the tuberculin-specific CD4 T-cell response with CMV serostatus. Our results show that how the immune system responds to CMV has a fundamental impact on the phenotype and function of the immune response to mycobacterial antigens in older life

Human cytomegalovirus infection in an as yet unexplored at-risk category of subjects: elderly subjects facing acute ischemic stroke

Background: Human cytomegalovirus (HCMV) is an important opportunistic pathogen leading to severe diseases in “at-risk” categories of individuals upon the symptomatic reactivation of the virus belonging to specific genotypes. In this respect, it has been postulated that envelope glycoproteins (g) N and O could have a key role as virulence factors, most likely in combined patterns. Several data is accumulating about HCMV reactivations in non-immunocompromised adults with critical illness that may impair clinical outcomes. The interplay between HCMV and immune surveillance is also supposed to become more vulnerable in advanced age; here, subclinical reactivations may drive expanded anti-HCMV immune responses. Accordingly, it is reasonable to expect cases of HCMV reactivation in elderly patients facing an acute life-threatening disease such as ischemic stroke. Materials/methods: We have performed an observational prospective study in a cohort of 105 elderly patients admitted to the Stroke Care Units of Parma University-Hospital for major acute ischemic stroke. Plasma samples from patients tested positive for anti-HCMV IgG, collected at 10±2 days from hospital admission, were analyzed for the presence of viral DNA by Real-Time PCR; gN and gO genotyping was performed by RFLP in case of positive DNAemia. Results: HCMV DNA was detected in the range of few hundred copies/mL in 11.7% of the analyzed samples. The gN and gO genotypes were characterized in 77.7% of the positive samples for HCMVDNAemia. In particular, the gN3 genotype was found to predominate (57.1%); with regard to gO, the recurrent genotypes were gO1 (57.1%) and gO2 (42.9%). Furthermore, these data suggest that combined gN3-gO1 and gN3-gO2 genotypes could be the recurring virulence factor patterns associated with viral DNAemia. Conclusions: This study focused for the first time on the role of HCMV infection in acute ischemic stroke. Overall, the results suggest that HCMV tends to escape immune surveillance in some elderly patients in this clinical setting. The quite low viral genome copies could be associated with localized, rather systemic, viral reactivations and involved specific HCMV envelope genotype combinations. The impact of these data will be evaluated with respect to clinical outcomes and HCMV-specific T cell responses of the studied population