The role of the thymus in immunosenescence: lessons from the study of thymectomized individuals

The thymus is the major site of T cell production and a key organ of the immune system. Its natural involution during the course of life has cast doubts as to its importance for the integrity of our immunity in adulthood. We provide here an overview of the recent works focusing on the immunological evaluation of subjects thymectomized during early childhood due to cardiac surgery of congenital heart defects. These studies represent new advances in our appreciation of the role of the thymus in humans and more generally in our understanding of the development of immunosenescence

Reduced naïve CD8+T-cell priming efficacy in elderly adults

International audienceAging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8 + T-cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling na€ ıve CD8 + T-cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8 + T-cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8 + T-cell responses specific for a model antigen. Reduced CD8 + T-cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the na€ ıve CD8 + T-cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging

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-1β) 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

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

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

The Oxygen Paradox, the French Paradox, and age-related diseases

open46openDavies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, Henry J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A.Davies, Joanna M. S.; Cillard, Josiane; Friguet, Bertrand; Cadenas, Enrique; Cadet, Jean; Cayce, Rachael; Fishmann, Andrew; Liao, David; Bulteau, Anne-Laure; Derbré, Frédéric; Rébillard, Amélie; Burstein, Steven; Hirsch, Etienne; Kloner, Robert A.; Jakowec, Michael; Petzinger, Giselle; Sauce, Delphine; Sennlaub, Florian; Limon, Isabelle; Ursini, Fulvio; Maiorino, Matilde; Economides, Christina; Pike, Christian J.; Cohen, Pinchas; Salvayre, Anne Negre; Halliday, Matthew R.; Lundquist, Adam J.; Jakowec, Nicolaus A.; Mechta-Grigoriou, Fatima; Mericskay, Mathias; Mariani, Jean; Li, Zhenlin; Huang, David; Grant, Ellsworth; Forman, HENRY J.; Finch, Caleb E.; Sun, Patrick Y.; Pomatto, Laura C. D.; Agbulut, Onnik; Warburton, David; Neri, Christian; Rouis, Mustapha; Cillard, Pierre; Capeau, Jacqueline; Rosenbaum, Jean; Davies, Kelvin J. A

Intracellular expression of Tat alters mitochondrial functions in T cells: a potential mechanism to understand mitochondrial damage during HIV-1 replication

HIV-1 replication results in mitochondrial damage that is enhanced during antiretroviral therapy (ART). The onset of HIV-1 replication is regulated by viral protein Tat, a 101-residue protein codified by two exons that elongates viral transcripts. Although the first exon of Tat (aa 1–72) forms itself an active protein, the presence of the second exon (aa 73–101) results in a more competent transcriptional protein with additional functions. Results: Mitochondrial overall functions were analyzed in Jurkat cells stably expressing full-length Tat (Tat101) or one-exon Tat (Tat72). Representative results were confirmed in PBLs transiently expressing Tat101 and in HIV-infected Jurkat cells. The intracellular expression of Tat101 induced the deregulation of metabolism and cytoskeletal proteins which remodeled the function and distribution of mitochondria. Tat101 reduced the transcription of the mtDNA, resulting in low ATP production. The total amount of mitochondria increased likely to counteract their functional impairment. These effects were enhanced when Tat second exon was expressed. Conclusions: Intracellular Tat altered mtDNA transcription, mitochondrial content and distribution in CD4+ T cells. The importance of Tat second exon in non-transcriptional functions was confirmed. Tat101 may be responsible for mitochondrial dysfunctions found in HIV-1 infected patients.We greatly appreciate the secretarial assistance of Mrs Olga Palao. This work was supported by FIPSE (360924/10), Spanish Ministry of Economy and Competitiveness (SAF2010-18388), Spanish Ministry of Health (EC11- 285), AIDS Network ISCIII-RETIC (RD12/0017/0015), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness (FIS PI12/00506). The work of Sara Rodríguez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness (2013). The work of María Rosa López-Huertas is supported by a fellowship of the European Union Programme Health 2009 (CHAARM).S

Assessing immune aging in HIV-infected patients

International audienc