Frailty is related to serum inflammageing markers: results from the VITAL study.

Frailty describes an age-associated state in individuals with an increased vulnerability and less resilience against adverse outcomes. To score frailty, studies have employed the questionnaires, such as the SF-36 and EQ-5D-3L, or the Frailty Index, a composite score based on deficit accumulation. Furthermore, ageing of the immune system is often accompanied by a state of low-grade inflammation (inflammageing). Here, we aimed to associate 29 circulating markers of inflammageing with frailty measures in a prospective cohort study to understand the mechanisms underlying ageing.Frailty measures and inflammageing markers were assessed in 317 participants aged 25-90. We determined four different measures of frailty: the Frailty Index based on 31 deficits, the EQ-5D-3L and two physical domains of the SF-36. Serum/plasma levels of inflammageing markers and CMV/EBV seropositivity were measured using different techniques: Quanterix, Luminex or ELISA.All four measures of frailty strongly correlated with age and BMI. Nineteen biomarkers correlated with age, some in a linear fashion (IL-6, YKL-40), some only in the oldest age brackets (CRP), and some increased at younger ages and then plateaued (CCL2, sIL-6R). After correcting for age, biomarkers, such as IL-6, CRP, IL-1RA, YKL-40 and elastase, were associated with frailty. When corrected for BMI, the number of associations reduced further.In conclusion, inflammageing markers, particularly markers reflecting innate immune activation, are related to frailty. These findings indicate that health decline and the accumulation of deficits with age is accompanied with a low-grade inflammation which can be detected by specific inflammatory markers.

Mechanisms of immune aging in HIV.

Massive CD4+ T-cell depletion as well as sustained immune activation and inflammation are hallmarks of Human Immunodeficiency Virus (HIV)-1 infection. In recent years, an emerging concept draws an intriguing parallel between HIV-1 infection and aging. Indeed, many of the alterations that affect innate and adaptive immune subsets in HIV-infected individuals are reminiscent of the process of immune aging, characteristic of old age. These changes, of which the presumed cause is the systemic immune activation established in patients, likely participate in the immuno-incompetence described with HIV progression. With the success of antiretroviral therapy (ART), HIV-seropositive patients can now live for many years despite chronic viral infection. However, acquired immunodeficiency syndrome (AIDS)-related opportunistic infections have given way to chronic diseases as the leading cause of death since HIV infection. Therefore, the comparison between HIV-1 infected patients and uninfected elderly individuals goes beyond the sole onset of immunosenescence and extends to the deterioration of several physiological functions related to inflammation and systemic aging. In light of this observation, it is interesting to understand the precise link between immune activation and aging in HIV-1 infection to figure out how to best care for people living with HIV (PLWH).

Distinct cytokine profiles associated with COVID-19 severity and mortality.

BACKGROUND: Markedly elevated levels of proinflammatory cytokines and defective type-I interferon responses were reported in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: We sought to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. METHODS: Cytokine concentrations and severe acute respiratory syndrome coronavirus 2 antigen were measured at hospital admission in serum of symptomatic patients with COVID-19 (N = 115), classified at hospitalization into 3 respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS), and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal-component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N = 86). RESULTS: At time of hospitalization, ECMO patients presented a dominant proinflammatory response with elevated levels of TNF-α, IL-6, IL-8, and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-ß was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at 1 month was associated with higher levels of proinflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients, and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (risk ratio, 24.3; P < .0001). Severe acute respiratory syndrome coronavirus 2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with proinflammatory response or severity. CONCLUSIONS: Distinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality according to oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.

New Insights into Lymphocyte Differentiation and Aging from Telomere Length and Telomerase Activity Measurements.

αß CD8+, γδ, and NK lymphocytes are fundamental effector cells against viruses and tumors. These cells can be divided into multiple subsets according to their phenotype. Based on progressive telomere attrition from naive to late effector memory cells, human CD8+ T cell subsets have been positioned along a pathway of differentiation, which is also considered as a process of lymphocyte aging or senescence. A similar categorization has not been clearly established for γδ and NK cell populations. Moreover, the distinction between the aging of these populations due to cellular differentiation or due to the chronological age of the donor has not been formally considered. In this study, we performed systematic measurements of telomere length and telomerase activity in human αß CD8+, γδ, and NK lymphocytes based on subset division and across age to address these points and better understand the dichotomy between differentiation and temporal aging. This approach enables us to position phenotypically distinct γδ or NK subsets along a putative pathway of differentiation, such as for CD8+ T cells. Moreover, our data show that both cellular differentiation and donor aging have profound but independent effects on telomere length and telomerase activity of lymphocyte subpopulations, implying distinct mechanisms and consequences on the immune system.

Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells.

Human herpesvirus 6 (HHV-6) infects >90% of the population and establishes a latent infection with asymptomatic episodes of reactivation. However, HHV-6 reactivation is associated with morbidity and sometimes mortality in immunocompromised patients. To date, control of the virus in healthy virus carriers and the failure to control it in patients with disease remain poorly understood. In particular, knowledge of HHV-6-specific T-cell responses is limited. Here, we characterized HHV-6A- and HHV-6B-specific CD4+ and CD8+ T-cell responses from peripheral blood mononuclear cells (PBMCs) of healthy donors. We studied the phenotype of effector HHV-6-specific T cells ex vivo, as well as of induced specific suppressive regulatory CD4+ T cells in vitro poststimulation, in comparison to human cytomegalovirus (HCMV) responses. Compared to that for HCMV, we show that ex vivo T-cell reactivity in peripheral blood is detectable but at very low frequency, both for HHV-6A and -6B viruses. Interestingly, the phenotype of the specific T cells also differs between the viruses. HHV-6A- and HHV-6B-specific CD4+ T lymphocytes are less differentiated than HCMV-specific T cells. Furthermore, we show a higher frequency of HHV-6-specific suppressive regulatory T cells (eTregs) than HCMV-specific eTregs in coinfected individuals. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection.IMPORTANCE T cells are central to an effective defense against persistent viral infections that can be related to human cytomegalovirus (HCMV) or human herpesvirus 6 (HHV-6). However, knowledge of HHV-6-specific T-cell responses is limited. In order to deepen our knowledge of T-cell responses to HHV-6, we characterized HHV-6A- and HHV-6B-specific CD4+ and CD8+ T-cell responses directly ex vivo from healthy coinfected blood donors. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection. Our findings may encourage immunomonitoring of patients with viral replication episodes to follow the emergence of effector versus regulatory T cells.

The hallmarks of CMV-specific CD8 T-cell differentiation.

Upon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T-cell response, CMV-specific T cells seem to have a distinctive phenotype, characterized by an advanced differentiation state. Here, we will review this "special" differentiation status by discussing the cellular phenotype based on the expression of CD45 isoforms, costimulatory, inhibitory and natural killer receptors, adhesion and lymphocyte homing molecules, transcription factors, cytokines and cytotoxic molecules. In addition, we focus on whether the differentiation state of CMV-specific CD8 T cells is unique in comparison with other chronic viruses and we will discuss the possible impact of factors such as antigen exposure and aging on the advanced differentiation status of CMV-specific CD8 T cells.

Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2-Infected Controllers.

Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we studied the production of CD8(+) T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort. HIV-2 controllers display a robust capacity to support long-term renewal of the CD8(+) T cell compartment by preserving immune resources, including hematopoietic progenitors and thymic activity, which could contribute to the long-term maintenance of the CD8(+) T cell response and the avoidance of premature immune aging. Our data support the presence of HIV-2 Gag-specific CD8(+) T cells that display an early memory differentiation phenotype and robust effector potential in HIV-2 controllers. Accordingly, to our knowledge, we show for the first time that HIV-2 controllers possess CD8(+) T cells that show an unusually strong capacity to suppress HIV-2 infection in autologous CD4(+) T cells ex vivo, an ability that likely depends on the preservation of host immune resources. This effective and durable antiviral response probably participates in a virtuous circle, during which controlled viral replication permits the preservation of potent immune functions, thus preventing HIV-2 disease progression.

Aging of the immune system: Focus on inflammation and vaccination.

Major advances in preventing, delaying, or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching eight to nine decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T-cell or B-cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.

Coordinated expansion of both memory T cells and NK cells in response to CMV infection in humans.

NK cells are key players in the fight against persistent viruses. Human cytomegalovirus (HCMV) infection is associated with the presence of a population of CD16(+) CD56(dim) NKG2C(+) NK cells in both acutely and latently infected individuals. Here, we studied the nature of these terminally differentiated NK cells in different human populations infected with HCMV: healthy donors stratified by age, thymectomized individuals, pregnant women suffering from primary CMV infection, and lung transplant patients. Both CD16(+) CD56(dim) NK- and CD8 T-cell phenotypes as well as functional capacities were determined and stratified according to age and/or CMV event. Similarly to T-cell responsiveness, we observe an accumulation over time of NKG2C(+) NK cells, which preferentially expressed CD57. This accumulation is particularly prominent in elderly and amplified further by CMV infection. Latent HCMV infection (without replication) is sufficient for NKG2C(+) CD57(+) NK cells to persist in healthy individuals but is not necessarily required in old age. Collectively, the present work supports the emerging concept that CMV shapes both innate and adaptive immunity in humans.

Differential impact of age and cytomegalovirus infection on the γδ T cell compartment.

γδ T cells represent a subset of unconventional T lymphocytes that are known for their reactivity against different pathogens and considered as intermediate mediators between adaptive and innate immunity. We provide in this paper further insights underlying the changes that affect the γδ T cell compartment with advanced age in humans. We show that both aging and CMV infection impact independently on the γδ T cell compartment. Most γδ T cells are significantly affected by age and present a decreased frequency in the elderly. The decline of the γδ T cell pool appears to be independent from the activity of the thymus, arguing in favor of an extrathymic site of γδ T cell production in humans. Of note, CMV infection, which is directly associated with the activation of the pool of Vδ2(-) γδ T cells, promotes nonetheless the inflation of this compartment throughout life. CMV seropositivity accentuates further the accumulation of highly differentiated lymphocytes in Vδ2(-) γδ T cell subsets with time, in contrast to Vδ2(+) γδ T cells, which maintain a less differentiated phenotype. This is similar to the effect of CMV on αß T cells and suggests that γδ T cells may vary in differentiation phenotype according to distinct stimuli or pathogens.

Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults.

Reduced thymopoiesis and continuous mobilization of naive T cells into the effector-memory pool can lead to severe alterations of the naive T cell compartment. However, maintenance of the naive T cell population is essential to mount effective immune responses. Evidence of homeostatic regulation of naive T cells is currently debated in animal models. In humans, the situation remains unresolved, in particular with advanced age. In this study, we analyzed the CD4(+) and CD8(+) naive T cell compartments from elderly, young adults thymectomized during early childhood, and HIV-1-infected patients, which are characterized by T lymphocytopenia. We show a direct association between increased turnover and decreased frequency of naive T cells. Moreover, the IL-7-induced pathway was fully functional in naive T cells from elderly and young adults thymectomized during early childhood, who are characterized by elevated IL-7 plasma levels. Our findings support the establishment of homeostatic regulation of naive T cell proliferation in humans. This regulation is particularly active in lymphopenic hosts, such as elderly and thymectomized patients.

Low unspliced cell-associated HIV RNA in early treated adolescents living with HIV on long suppressive ART.

Introduction: Initiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population. Methods: Forty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested. Results: CA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-α was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study. Conclusions: Low CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation.

Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover.

The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)-B27 patients. To understand further the nature of CD8+ T cell-mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27-restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10-specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.

CMV driven CD8(+) T-cell activation is associated with acute rejection in lung transplantation.

Lung transplantation is the definitive treatment for terminal respiratory disease, but the associated mortality rate is high. Acute rejection of the transplanted lung is a key determinant of adverse prognosis. Furthermore, an epidemiological relationship has been established between the occurrence of acute lung rejection and cytomegalovirus infection. However, the reasons for this association remain unclear. Here, we performed a longitudinal characterization of CMV-specific T-cell responses and immune activation status in the peripheral blood and bronchoalveolar lavage fluid of forty-four lung transplant patients. Acute rejection was associated with high levels of cellular activation in the periphery, reflecting strong CMV-specific CD8(+) T-cell activity post-transplant. Peripheral and lung CMV-specific CD8(+) T-cell responses were very similar, and related to the presence of CMV in the transplanted organ. These findings support that activated CMV-specific CD8(+) T-cells in the lung may play a role in promoting acute rejection.

Exhausted cytotoxic control of Epstein-Barr virus in human lupus.

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1ß) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis.

The mechanisms of CD4(+) T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4(+) T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4(+) T-cell levels probably depends primarily on the capacity to renew depleted lymphocytes, that is, the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34(+) hematopoietic progenitor cells directly from the blood of a large set of HIV-infected persons compared with uninfected donors, in particular the elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virologic success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.

Expression of immune checkpoint on subset of monocytes in old patients.

BACKGROUND: Immune checkpoints and their ligands are important actors of lymphocytes and monocytes activation's regulation. Their expression level within T cells changes with aging. Despite the major impact of aging on monocytes, there is no data about the expression of ICs on monocytes from old patients. The objective of our study is to describe the expression of ICs and their ligands on monocytes from young individuals compared to old patients. METHODS: We included 18 old control (>75 years old), 10 young control (<55 years old) and 45 old patients with hip fracture (HF). Phenotypical and functional analyses were performed on cryopreserved PBMCs. RESULTS: There is a differential expression of immune checkpoints and their ligands within monocyte subtypes regardless of age at baseline. After stimulation, a differential expression of immune checkpoints in young subjects but not in old subjects was observed which would be in favor of a regulation defect in old subjects. We hypothesize that this lack of regulation could partially explain the excess production of pro-inflammatory cytokines by the stimulated monocytes in old subjects. In HF, we also observe a differential expression of immune checkpoints, especially in old patients with a poor prognosis. CONCLUSION: Our results suggest that the immune regulation which should take place post-acute stress may be affected in old individuals.

IL-7 producing immunotherapy improves ex vivo T cell functions of immunosenescent patients, especially post hip fracture.

Following acute stress such as trauma or sepsis, most of critically ill elderly patients become immunosuppressed and susceptible to secondary infections and enhanced mortality. We have developed a virus-based immunotherapy encoding human interleukin-7 (hIL-7) aiming at restoring both innate an adaptative immune homeostasis in these patients. We assessed the impact of this encoded hIL-7 on the ex vivo immune functions of T cells from PBMC of immunosenescent patients with or without hip fracture. T-cell ex vivo phenotyping was characterized in terms of senescence (CD57), IL-7 receptor (CD127) expression, and T cell differentiation profile. Then, post stimulation, activation status, and functionality (STAT5/STAT1 phosphorylation and T cell proliferation assays) were evaluated by flow cytometry. Our data show that T cells from both groups display immunosenescence features, express CD127 and are activated after stimulation by virotherapy-produced hIL-7-Fc. Interestingly, hip fracture patients exhibit a unique functional ability: An important T cell proliferation occurred compared to controls following stimulation with hIL-7-Fc. In addition, stimulation led to an increased naïve T cell as well as a decreased effector memory T cell proportions compared to controls. This preliminary study indicates that the produced hIL-7-Fc is well recognized by T cells and initiates IL-7 signaling through STAT5 and STAT1 phosphorylation. This signaling efficiently leads to T cell proliferation and activation and enables a T cell "rejuvenation." These results are in favor of the clinical development of the hIL-7-Fc expressing virotherapy to restore or induce immune T cell responses in immunosenescent hip fracture patients.

Multiparameter grouping delineates heterogeneous populations of human IL-17 and/or IL-22 T-cell producers that share antigen specificities with other T-cell subsets.

The ontogenic relationship between pro-inflammatory populations of interleukin-17 (IL-17A)- and/or IL-22-producing T cells and other T-cell subsets is currently unclear in humans. To appreciate T helper cell-lineage commitment, we combined cytokine production profiles of in vitro expanded T-cell clones with T-cell receptor (TCR) clonotypic signatures. Moreover, ex vivo cytokine production profiles at the single-cell level were analyzed using an original approach based on the hierarchical cluster analysis of multiparametric flow cytometry data. These combined approaches enabled the delineation of distinct functional T-cell subsets, including Th1, Th2, Tr1, Th17 cells and a highly polyfunctional IL-22-producing T-cell population. Cluster analysis highlighted that the IL-22-producing T-cell population should be considered independently from the Th17 and Th1 subsets, although it was more closely related to the former. In parallel, we observed extensive TCRαß sharing across all five subsets defined. The strategy described here allows the objective definition of cellular subsets and an unbiased insight into their similarities. Together, our results underscore the ontogenic plasticity of CD4(+) T-cell progenitors, which can adopt a differentiation profile irrespective of antigen specificity.

CMV and Immunosenescence: from basics to clinics.

Alone among herpesviruses, persistent Cytomegalovirus (CMV) markedly alters the numbers and proportions of peripheral immune cells in infected-vs-uninfected people. Because the rate of CMV infection increases with age in most countries, it has been suggested that it drives or at least exacerbates "immunosenescence". This contention remains controversial and was the primary subject of the Third International Workshop on CMV & Immunosenescence which was held in Cordoba, Spain, 15-16th March, 2012. Discussions focused on several main themes including the effects of CMV on adaptive immunity and immunosenescence, characterization of CMV-specific T cells, impact of CMV infection and ageing on innate immunity, and finally, most important, the clinical implications of immunosenescence and CMV infection. Here we summarize the major findings of this workshop.