Emergence of a CD4+CD28- Granzyme B+, Cytomegalovirus-Specific T Cell Subset after Recovery of Primary Cytomegalovirus Infection (original) (raw)
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CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection
F1000Research
Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells.
Arthritis Research & Therapy, 2010
Introduction: Anti-tumor necrosis factor (TNF)-α biotherapies have considerably changed the treatment of rheumatoid arthritis (RA). However, serious infections are a major concern in patients with rheumatic diseases treated with anti-TNF-α. Little is known about viral, especially latent, infections in anti-TNF-α treatments. Infections by cytomegalovirus (CMV), a β-herpes virus, are frequent and induce a strong CD4 pos T-cell immunity, which participates in the control of infection. We thus have chosen to analyze the CD4 pos T-cell response to CMV antigens as a model of antiviral response in RA patients treated with anti-TNF-α. CD28 expression was evaluated. Methods: We have measured the CD4 pos response to CMV antigens in RA patients, before and after initiation of treatment with an anti-TNF-α agent. The intracellular production of interferon (IFN)-γ in total and CD28 neg CD4 pos T cells in response to CMV antigens (Ags) was evaluated with flow cytometry. The proliferation of total CD4 pos T cells in the presence of CMV antigens was measured with 3 H-thymidine incorporation. Results: Anti-TNF-α treatments impaired neither the anti-CD4 pos anti-CMV IFN-γ response nor the proliferative response in patients. The percentage of CD28 neg CD4 pos cells remained constant. Conclusions: Our data suggest that the CD4 pos T-cell response against CMV is not altered by anti-TNF-α treatments and that infection remains controlled in treated RA patients latently infected with CMV. Our observation brings new insight into the current knowledge of the risks of infection in patients treated with anti-TNF-α biotherapies.
Scientific Reports
In people living with HIV (PLWHIV), coinfection with cytomegalovirus (CMV) has been associated with inflammation, immunological ageing, and increased risk of severe non-AIDS related comorbidity. The effect of CMV-specific immune responses on systemic inflammation, immune activation and T-cell senescence was evaluated in 53 PLWHIV treated with combination antiretroviral therapy (cART). Activated-, terminally differentiated-, naïve-, and senescent T-cells were assessed by flow cytometry, and plasma levels of CMV IgG, interleukin-6, tumor necrosis factor-α, high-sensitivity C-reactive protein and soluble-CD14 were measured. In PLWHIV, expression of interleukin-2, tumor necrosis factor-α and interferon-γ was measured by intracellular-cytokine-staining after stimulation of T-cells with CMV-pp65, CMV-IE1, and CMV-gB. Increased CMV-specific T-cell responses were associated with a higher ratio of terminally differentiated/naïve CD8+ T-cells and with increased proportions of senescent CD8+ T-cells, but not with systemic inflammation or sCD14. Increased CMV-specific CD4+ T-cell responses were associated with increased proportions of activated CD8+ T-cells. In PLWHIV with expansion of CMV-specific T-cells or increased T-cell senescence, CMV-specific polyfunctionality was maintained. That the magnitude of the CMV-specific T-cell response was associated with a senescent immune phenotype, suggests that a dysregulated immune response against CMV may contribute to the immunological ageing often described in PLWHIV despite stable cART. After introduction of combination antiretroviral therapy (cART), life expectancy has increased for people living with HIV (PLWHIV) 1-3 , but has not yet reached that of the background population 4. Non-AIDS comorbidity contributes to the gap in life expectancy, and PLWHIV on stable cART have increased risk for early onset of age-related diseases including cardiovascular diseases and renal diseases 5. This is probably due to complex interactions between HIV infection itself, traditional risk factors, and other factors such as coinfection with cytomegalovirus (CMV), residual immune dysfunction, and inflammation 6,7. The majority of PLWHIV are coinfected with CMV, a common β-herpes virus that establishes lifelong latent infection with frequent asymptomatic reactivations 8. In PLWHIV, the presence of CMV coinfection has been associated with increased risk of inflammation, phenotypic T-cell alterations, and non-AIDS comorbidities 9-15. CMV seropositivity in PLWHIV have been associated with expansion of CD8+ T-cells, a reduced CD4+/CD8+ T-cell ratio, and increased levels of CD8+ T-cell senescence markers 9,10,12,14,16. Characteristics that independently have been associated with increased morbidity and mortality 17-19. The immunological mechanisms are incompletely understood, and it has been suggested that not only CMV infection itself but also the host's immune
Rheumatology international, 2017
Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4(+)CD28(null) T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4(+)CD28(null) T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4(+)CD28(null) T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviati...
Journal of General Virology, 2011
Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naïve CD8 + T-cells and a higher fraction of late-differentiated CD8 + cells, commonly taken as biomarkers of age-associated compromised adaptive immunity ('immunosenescence'), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established. Here, we analysed T-cell subsets in 93 healthy people aged 42-81 years infected or not infected with CMV and/or HSV. Individuals harbouring CMV were confirmed to possess lower frequencies of naïve CD8 + T-cells (defined as CD45RA + CCR7 + CD27 + CD28 + ) and greater proportions of late-differentiated effector memory (CD45RA " CCR7 " CD27 " CD28 " ) and so-called TEMRA (CD45RA + CCR7 " CD27 " CD28 " ) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly. We conclude that these hallmarks of age-associated alterations to immune signatures are indeed observed in the general population in people infected with CMV and not those infected with a different persistent herpesvirus.
Human Immunology, 2007
Despite general acceptance that immunologic changes are associated with aging and latent infection with Cytomegalovirus (CMV), no clear-cut distinction has so far been made between strictly agerelated and CMV-induced changes. We therefore compared CD4 ϩ and CD8 ϩ naïve (CD45RAϩCD28ϩ), memory (CD45RAϪCD28ϩ), and effector (CD28 Ϫ ) T cells in CMV-positive (n ϭ 164) and CMV-negative (n ϭ 87) elderly persons and correlated CD8 ϩ and CD4 ϩ effector T cells with other T-cell subpopulations. Percentages of CD8 ϩ as well as CD4 ϩ effector T cells were higher, but percentages of naïve and memory cells were lower in CMV-positive compared to CMV-negative elderly persons. Negative correlations within CD8 ϩ Tcell subsets were found to be present in both CMVpositive and CMV-negative elderly individuals. In contrast, correlations within CD4 ϩ T-cell subpopulations and a positive correlation between CD8 ϩ and CD4 ϩ effector T cells were found in CMV-positive individuals only. Our results demonstrate that (a) in the elderly different T-cell subsets compete for space within the CD8 ϩ , but not the CD4 ϩ T-cell population; (b) CMV induces changes in the CD4 ϩ compartment that differ from the solely agerelated changes seen in CMV-negative elderly population; and (c) the CMV-status of a population has to be taken into account before a conclusion on the effect of aging on the composition of the T-cell pool can be reached. Human Immunology 68, 86 -90 (2007).