La protéine TRF2 est une protéine clé dans la dynamique des télomères, ces structures nucléoprotéiques présentes à l'extrémité des chromosomes linéaires et responsables de leur protection. Bien que la manière dont les télomères s'organisent pour protéger l'ADN soit encore méconnue, il a été montré récemment que TRF2 est à l'origine de la formation d'une structure en boucle, ou boucle télomérique qui empêcherait les extrémités télomériques d'être reconnus comme des coupures double brin. Un modèle propose que TRF2 permette la formation de cette boucle en induisant l'invasion du simple brin télomérique terminal à l'intérieur de la séquence double brin après repliement du télomère sur lui même. Les études réalisées lors de cette thèse montrent que TRF2 est en mesure de stimuler l'invasion télomérique de manière indirecte facilitant l'ouverture de la double hélice grâce à des modifications d'ordre topologique de l'ADN cible. Par ailleurs, les travaux réalisés mettent également en évidence un second mode de fixation à l'ADN de TRF2, par l'intermédiaire de son domaine N-terminal qui possède une affinité remarquable pour la structure des jonctions de Holliday. La dernière partie de cette thèse met en évidence l'activité 5' exonucléase d'une nouvelle protéine télomérique, la protéine Apollon, qui serait impliquée dans la protection des télomères. Tous ces résultats participent à une meilleure compréhension du fonctionnement de TRF2 sur les télomères et en particulier de son rôle dans la formation de la boucle télomérique.

T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases.

CD4 T cell homeostasis and competency are critical for the effectiveness of antiviral immunity. However, CD4 T cells derived from people living with HIV (PLWH) and individuals with chronic HCV infection often exhibit an inflammaging phenotype, evidenced by persistent inflammation, immune activation, exhaustion, senescence, and cellular apoptosis. Despite intensive investigations, the molecular mechanisms underlying CD4 T cell dysfunction in antiretroviral therapy (ART)-controlled PLWH and HCV-infected patients remain poorly understood. By investigating the roles of non-coding (nc)RNA transcripts in regulating the functions of CD4 T cells derived from PLWH and HCV-infected patients, we demonstrated that long non-coding (lnc)RNA - growth arrest-specific transcript 5 (GAS5) - is downregulated and plays a crucial role in regulating CD4 T cell functions through and beyond the microRNA (miR)-21-mediated signaling network. Our data suggest that disrupting the GAS5-miR21 axis may restore CD4 T cell homeostasis and competency during latent HIV infection and prevent premature CD4 T cell aging or immune senescence. Moreover, our results also showed that TRF2, a component of the shelterin complex maintaining the integrity of telomeres, is post-transcriptionally inhibited, which is one of the major forces driving cellular dysregulation in CD4 T cells from PLWH and HCV patients. Importantly, our study identified miR-23a as the key regulator of TRF2 translational expression by targeting its 3’UTR in CD4 T cells and that targeting miR-23a may restore the TRF2 protein level, and thereby reconstitute CD4 T cell homeostasis and competency to rescue CD4 T cells from premature aging and immunosenescence during latent HIV infection. The findings from these studies improved our understanding and knowledge of how ncRNA-mediated networks regulate the functions of CD4 T cells during chronic viral (HIV and HCV) infections. Understanding such mechanisms is important for developing therapeutic approaches to reverse the inflammaging phenotype observed in CD4 T cells from ART-controlled PLWH and chronically HCV-infected patients to improve their immunological functions and quality of life.

No description available.

Les télomères sont des structures nucléoprotéiques localisées aux extrémités des chromosomes. Ils jouent un rôle important dans le maintien de l’information génétique, la stabilité et la protection des extrémités chromosomiques. Les télomères sont composés de séquences d’ADN répétées riches en guanines (TTAGGG) et des protéines télomériques qui les protègent. Parmi celles-ci, TRF1 et TRF2 se fixent directement sur le double brin. Toute modification de la structure des télomères (composition en protéines télomériques, raccourcissement de leur longueur, dommages) peut entrainer la mort des cellules cancéreuses. Ainsi les télomères sont considérés comme des cibles thérapeutiques. Etant riches en guanines adjacentes, les télomères sont donc des cibles potentielles du cis-platine, agent pharmacologique utilisé dans le traitement d’un certain nombre de tumeurs. Nous avons analysé, sur deux lignées de cancer d’ovaire A2780 sensibles et résistantes au cis- platine, les modifications éventuelles de la structure de leurs télomères après traitement par le cis-platine et quantifié le cis-platine fixé au niveau des télomères afin de déterminer s’il pourrait être l’origine de ces perturbations. Suite au traitement par le cis-platine, une délocalisation de TRF2 des télomères (maximum 55%) a été mise en évidence dans les deux lignées, accompagnée de dommages au niveau des télomères (2-3 dommages/cellule) mais elle est cependant insuffisante pour induire leur raccourcissement. Ensuite, la quantification par ICP-MS du cis-platine fixé au niveau de l’ADN télomérique purifié montre que le cis-platine se fixe bien au niveau des télomères. Cependant cette quantité fixée est 5 fois moins importante que celle trouvée au niveau de l’ADN génomique et 12 fois moins importante que celle attendue d’après les études in vitro, suggérant que les guanines de l’ADN télomérique sont moins accessibles que celles de l’ADN génomique. D’autre part, la quantité de cis-platine fixé par base est trop faible pour expliquer le déplacement de TRF2. Ces résultats suggèrent que la fixation du cis-platine au niveau des télomères ne peut donc pas être le mécanisme majoritaire responsable du déplacement de TRF2 des télomères et de la mort des cellules. Ce travail ouvre ainsi la voie à la conception de nouveaux complexes anti-tumoraux de platine qui cibleraient plus spécifiquement les télomères des cellules cancéreuses afin de les déstructurer plus efficacement. / Telomeres are nucleoprotein structures located at the ends of chromosomes. They play an important role in the maintenance of the genetic information, the stability and protection of chromosome’s ends. Telomeres consist of repeated DNA sequences G-rich (TTAGGG)n, and telomeric proteins that protect them. Among them, TRF1 and TRF2 bind directly to double-stranded. Any change in the structure of telomeres (telomeric protein composition, shortening their length, damage) can cause the death of cancer cells. Thus telomeres are considered as therapeutic targets. Since they are rich in adjacent guanines, telomeres are therefore potential targets for cis-platin, a pharmacological agent used in the treatment of a certain number of tumours. We looked for, at the cellular level, using two lines of ovarian cancer A2780: sensitive and resistant to cis-platin any changes in the structure of their telomeres after cis-platin treatment. And we checked the amount of cis-platin bound to telomeres to determine if it could be the cause of these perturbations. Following treatment with cis-platin, a delocalisation of TRF2 from telomere (maximum 55%) was observed within both cell lines, with damages at telomeres (2-3 damages / cell). But it is still not enough to induce their shortening. Then, the quantification by ICP-MS of the cis-platin fixed at purified telomeric DNA, shows that cis-platin binds well at telomeres. However, this amount is 5 times less than that the one found at genomic DNA and 12 times less than the one expected from in vitro studies, suggesting that the guanines of the telomeric DNA are less accessible than those of the genomic DNA. On the other hand, the amount of cis-platin bound by base is too small to explain the displacement of TRF2. So, these results suggest that the binding of cis-platin at telomeres cannot be the principal mechanism responsible of cell death, and that the displacement of TRF2 from telomere is not related directly to this phenomenon. Thus, this work opens the way for the design of new anti-tumour platinum complexes that target telomeres of cancer cells more specifically, in order to induce more efficiently their dysfunction.

Overall, this study enhances our understanding of the role of c-Myc activation in chromosome 11 repositioning in mouse PreB v-abl/myc cells and a possible interaction between telomeres, TRF2, and lamin A/C underlying this phenomenon. Additionally, the importance of human 17q25.3 is confirmed as a potential region involved in NSCLC tumorigenesis. A utilizationof the 3D telomeric organization profiles is demonstrated a tendency to categorize NSCLC patients into different prognostic subgroups, underscoring a potential future value of its clinical application. / February 2017

Nos indivíduos com obesidade, o excesso de tecido adiposo, exerce um papel fundamental induzindo um estado inflamatório crônico e sistêmico. A obesidade mimetiza processos celulares semelhantes aos do envelhecimento tais como a deterioração de tecidos e órgãos e diminuição na capacidade de reparo dos danos induzidos ao DNA. Nesse contexto, as citocinas pró-inflamatórias induzem atritos ao DNA que impactam, principalmente nas regiões mais susceptíveis dos cromossomos, os telômeros. Os telômeros, presentes nas extremidades dos cromossomos, estão associados a um complexo proteico denominado complexo shelterin. O complexo shelterin é formado por 6 proteínas (TRF1, TRF2, TIN2, POT1, TPP1 e RAP1), que junto com proteínas acessórias como a disquerina (DKC1), participam da regulação do comprimento dos telômeros e protegem os cromossomos dede atividades indesejadas de erosão enzimática, recombinação não-homóloga e fusão das terminações cromossômicas. Nos últimos anos, foram estabelecidas relações positivas entre condições patológicas clinicamente diferentes, como as moduladas por inflamação, e o comprimento dos telômeros. Recentemente, nosso grupo demonstrou telômeros encurtados em indivíduos portadores de obesidade mórbida. Assim o objetivo do presente trabalho foi explorar fatores adicionais associados ao metabolismo telomérico, como a expressão gênica das proteínas do complexo shelterin e citocinas pró-inflamatórias, as quais podem contribuir para o encurtamento acelerado de telômeros. Utilizamos amostras de células mononucleares de sangue periférico (PBMC) de indivíduos adultos saudáveis (n = 27) e indivíduos adultos portadores de obesidade (n = 39). Quantificamos a expressão gênica por transcrição reversa e PCR quantitativa (RT-qPCR) de todos os genes do complexo shelterin, DKC1, IL-1β e TNF-α. Nossos resultados demonstram um perfil de expressão gênica alterado quando comparada a expressão gênica das proteínas analisadas nos dois grupos estudados, controles e portadores de obesidade. Os indivíduos portadores de obesidade mostraram um perfil significativamente elevado dos genes TRF1, POT1, RAP1 e DKC1 (P < 0,05). Não observamos correlação de expressão gênica entre os diferentes genes e o comprimento dos telômeros nos grupos estudados, mas sim com a DKC1 na obesidade. Entretanto, quando analisamos as associações entre os genes de complexo shelterin observamos mudanças significativas nas associações intra-grupo dependentes da condição de obesidade. Nossos resultados salientam a complexa e intrincada rede de fatores associados e desregulados durante o processo fisiopatológico da obesidade. Estudos adicionais serão necessários acrescentando novos fatores para tentar dissecar a regulação coordenada do comprimento dos telômeros na homeostase e no processo patológico da obesidade. / In individuals with obesity, the excess of adipose tissue plays a key role in inducing a chronic and systemic inflammatory state. Like aging, obesity mimics cellular processes such as deterioration of tissues and organs and decreased ability to repair age-dependent DNA damages. In this context, the proinflammatory cytokines induce DNA damage that impact, especially in the most susceptible regions of the chromosomes, the telomeres. The telomeres, present at the ends of the chromosomes, are associated with a protein complex called the shelterin complex. The shelterin complex consists of 6 proteins (TRF1, TRF2, TIN2, POT1, TPP1 and RAP1), which together with accessory proteins such as dyskerin (DKC1), participate in telomere’s length regulation and protect chromosomes from undesired erosion, enzymatic activities, non-homologous recombination and fusion of chromosomal terminations. In recent years, positive relationships have been established between clinically different pathological conditions, such as those modulated by inflammation, and telomeres’ length. Recently, our group demonstrated shortened telomeres in individuals with morbid obesity. Thus, the aim of the present study was to explore additional factors associated with telomeres’ metabolism, such as gene expression of the shelterin complex components and proinflammatory cytokines, which may contribute to the accelerated shortening of the telomeres. We used peripheral blood mononuclear cells (PBMC) samples from healthy adults (n = 27) and adults with obesity (n = 39). We quantified gene expression by reverse transcription and quantitative PCR (RT-qPCR) of all shelterin complex genes, DKC1, IL-1β and TNF-α. Our results demonstrate an altered gene expression profile when compared to the gene expression of the proteins analyzed in the two studied groups, controls and individuals with obesity. Individuals with obesity showed a significantly elevated profile of TRF1, POT1, RAP1 and DKC1 (P < 0.05) genes. We did not observe correlation of gene expression between the different shelterin genes and the length of telomeres in the studied groups, but with DKC1 in obesity. However, when we analyzed the associations between the shelterin complex genes we observed significant changes in the intra-group associations dependent on the obesity condition. Our results highlight the complex and intricate network of associated and deregulated factors during the pathophysiological process of obesity. Further studies are needed together with the inclusion of additional factors to try to dissect the coordinated regulation of telomeres’ length in homeostasis and in the pathological process of obesity.

Nos indivíduos com obesidade, o excesso de tecido adiposo, exerce um papel fundamental induzindo um estado inflamatório crônico e sistêmico. A obesidade mimetiza processos celulares semelhantes aos do envelhecimento tais como a deterioração de tecidos e órgãos e diminuição na capacidade de reparo dos danos induzidos ao DNA. Nesse contexto, as citocinas pró-inflamatórias induzem atritos ao DNA que impactam, principalmente nas regiões mais susceptíveis dos cromossomos, os telômeros. Os telômeros, presentes nas extremidades dos cromossomos, estão associados a um complexo proteico denominado complexo shelterin. O complexo shelterin é formado por 6 proteínas (TRF1, TRF2, TIN2, POT1, TPP1 e RAP1), que junto com proteínas acessórias como a disquerina (DKC1), participam da regulação do comprimento dos telômeros e protegem os cromossomos dede atividades indesejadas de erosão enzimática, recombinação não-homóloga e fusão das terminações cromossômicas. Nos últimos anos, foram estabelecidas relações positivas entre condições patológicas clinicamente diferentes, como as moduladas por inflamação, e o comprimento dos telômeros. Recentemente, nosso grupo demonstrou telômeros encurtados em indivíduos portadores de obesidade mórbida. Assim o objetivo do presente trabalho foi explorar fatores adicionais associados ao metabolismo telomérico, como a expressão gênica das proteínas do complexo shelterin e citocinas pró-inflamatórias, as quais podem contribuir para o encurtamento acelerado de telômeros. Utilizamos amostras de células mononucleares de sangue periférico (PBMC) de indivíduos adultos saudáveis (n = 27) e indivíduos adultos portadores de obesidade (n = 39). Quantificamos a expressão gênica por transcrição reversa e PCR quantitativa (RT-qPCR) de todos os genes do complexo shelterin, DKC1, IL-1β e TNF-α. Nossos resultados demonstram um perfil de expressão gênica alterado quando comparada a expressão gênica das proteínas analisadas nos dois grupos estudados, controles e portadores de obesidade. Os indivíduos portadores de obesidade mostraram um perfil significativamente elevado dos genes TRF1, POT1, RAP1 e DKC1 (P < 0,05). Não observamos correlação de expressão gênica entre os diferentes genes e o comprimento dos telômeros nos grupos estudados, mas sim com a DKC1 na obesidade. Entretanto, quando analisamos as associações entre os genes de complexo shelterin observamos mudanças significativas nas associações intra-grupo dependentes da condição de obesidade. Nossos resultados salientam a complexa e intrincada rede de fatores associados e desregulados durante o processo fisiopatológico da obesidade. Estudos adicionais serão necessários acrescentando novos fatores para tentar dissecar a regulação coordenada do comprimento dos telômeros na homeostase e no processo patológico da obesidade. / In individuals with obesity, the excess of adipose tissue plays a key role in inducing a chronic and systemic inflammatory state. Like aging, obesity mimics cellular processes such as deterioration of tissues and organs and decreased ability to repair age-dependent DNA damages. In this context, the proinflammatory cytokines induce DNA damage that impact, especially in the most susceptible regions of the chromosomes, the telomeres. The telomeres, present at the ends of the chromosomes, are associated with a protein complex called the shelterin complex. The shelterin complex consists of 6 proteins (TRF1, TRF2, TIN2, POT1, TPP1 and RAP1), which together with accessory proteins such as dyskerin (DKC1), participate in telomere’s length regulation and protect chromosomes from undesired erosion, enzymatic activities, non-homologous recombination and fusion of chromosomal terminations. In recent years, positive relationships have been established between clinically different pathological conditions, such as those modulated by inflammation, and telomeres’ length. Recently, our group demonstrated shortened telomeres in individuals with morbid obesity. Thus, the aim of the present study was to explore additional factors associated with telomeres’ metabolism, such as gene expression of the shelterin complex components and proinflammatory cytokines, which may contribute to the accelerated shortening of the telomeres. We used peripheral blood mononuclear cells (PBMC) samples from healthy adults (n = 27) and adults with obesity (n = 39). We quantified gene expression by reverse transcription and quantitative PCR (RT-qPCR) of all shelterin complex genes, DKC1, IL-1β and TNF-α. Our results demonstrate an altered gene expression profile when compared to the gene expression of the proteins analyzed in the two studied groups, controls and individuals with obesity. Individuals with obesity showed a significantly elevated profile of TRF1, POT1, RAP1 and DKC1 (P < 0.05) genes. We did not observe correlation of gene expression between the different shelterin genes and the length of telomeres in the studied groups, but with DKC1 in obesity. However, when we analyzed the associations between the shelterin complex genes we observed significant changes in the intra-group associations dependent on the obesity condition. Our results highlight the complex and intricate network of associated and deregulated factors during the pathophysiological process of obesity. Further studies are needed together with the inclusion of additional factors to try to dissect the coordinated regulation of telomeres’ length in homeostasis and in the pathological process of obesity.

Nos indivíduos com obesidade, o excesso de tecido adiposo, exerce um papel fundamental induzindo um estado inflamatório crônico e sistêmico. A obesidade mimetiza processos celulares semelhantes aos do envelhecimento tais como a deterioração de tecidos e órgãos e diminuição na capacidade de reparo dos danos induzidos ao DNA. Nesse contexto, as citocinas pró-inflamatórias induzem atritos ao DNA que impactam, principalmente nas regiões mais susceptíveis dos cromossomos, os telômeros. Os telômeros, presentes nas extremidades dos cromossomos, estão associados a um complexo proteico denominado complexo shelterin. O complexo shelterin é formado por 6 proteínas (TRF1, TRF2, TIN2, POT1, TPP1 e RAP1), que junto com proteínas acessórias como a disquerina (DKC1), participam da regulação do comprimento dos telômeros e protegem os cromossomos dede atividades indesejadas de erosão enzimática, recombinação não-homóloga e fusão das terminações cromossômicas. Nos últimos anos, foram estabelecidas relações positivas entre condições patológicas clinicamente diferentes, como as moduladas por inflamação, e o comprimento dos telômeros. Recentemente, nosso grupo demonstrou telômeros encurtados em indivíduos portadores de obesidade mórbida. Assim o objetivo do presente trabalho foi explorar fatores adicionais associados ao metabolismo telomérico, como a expressão gênica das proteínas do complexo shelterin e citocinas pró-inflamatórias, as quais podem contribuir para o encurtamento acelerado de telômeros. Utilizamos amostras de células mononucleares de sangue periférico (PBMC) de indivíduos adultos saudáveis (n = 27) e indivíduos adultos portadores de obesidade (n = 39). Quantificamos a expressão gênica por transcrição reversa e PCR quantitativa (RT-qPCR) de todos os genes do complexo shelterin, DKC1, IL-1β e TNF-α. Nossos resultados demonstram um perfil de expressão gênica alterado quando comparada a expressão gênica das proteínas analisadas nos dois grupos estudados, controles e portadores de obesidade. Os indivíduos portadores de obesidade mostraram um perfil significativamente elevado dos genes TRF1, POT1, RAP1 e DKC1 (P < 0,05). Não observamos correlação de expressão gênica entre os diferentes genes e o comprimento dos telômeros nos grupos estudados, mas sim com a DKC1 na obesidade. Entretanto, quando analisamos as associações entre os genes de complexo shelterin observamos mudanças significativas nas associações intra-grupo dependentes da condição de obesidade. Nossos resultados salientam a complexa e intrincada rede de fatores associados e desregulados durante o processo fisiopatológico da obesidade. Estudos adicionais serão necessários acrescentando novos fatores para tentar dissecar a regulação coordenada do comprimento dos telômeros na homeostase e no processo patológico da obesidade. / In individuals with obesity, the excess of adipose tissue plays a key role in inducing a chronic and systemic inflammatory state. Like aging, obesity mimics cellular processes such as deterioration of tissues and organs and decreased ability to repair age-dependent DNA damages. In this context, the proinflammatory cytokines induce DNA damage that impact, especially in the most susceptible regions of the chromosomes, the telomeres. The telomeres, present at the ends of the chromosomes, are associated with a protein complex called the shelterin complex. The shelterin complex consists of 6 proteins (TRF1, TRF2, TIN2, POT1, TPP1 and RAP1), which together with accessory proteins such as dyskerin (DKC1), participate in telomere’s length regulation and protect chromosomes from undesired erosion, enzymatic activities, non-homologous recombination and fusion of chromosomal terminations. In recent years, positive relationships have been established between clinically different pathological conditions, such as those modulated by inflammation, and telomeres’ length. Recently, our group demonstrated shortened telomeres in individuals with morbid obesity. Thus, the aim of the present study was to explore additional factors associated with telomeres’ metabolism, such as gene expression of the shelterin complex components and proinflammatory cytokines, which may contribute to the accelerated shortening of the telomeres. We used peripheral blood mononuclear cells (PBMC) samples from healthy adults (n = 27) and adults with obesity (n = 39). We quantified gene expression by reverse transcription and quantitative PCR (RT-qPCR) of all shelterin complex genes, DKC1, IL-1β and TNF-α. Our results demonstrate an altered gene expression profile when compared to the gene expression of the proteins analyzed in the two studied groups, controls and individuals with obesity. Individuals with obesity showed a significantly elevated profile of TRF1, POT1, RAP1 and DKC1 (P < 0.05) genes. We did not observe correlation of gene expression between the different shelterin genes and the length of telomeres in the studied groups, but with DKC1 in obesity. However, when we analyzed the associations between the shelterin complex genes we observed significant changes in the intra-group associations dependent on the obesity condition. Our results highlight the complex and intricate network of associated and deregulated factors during the pathophysiological process of obesity. Further studies are needed together with the inclusion of additional factors to try to dissect the coordinated regulation of telomeres’ length in homeostasis and in the pathological process of obesity.

Chronic hepatitis C virus (HCV) infection exhibits persistent high viral load, inducing T cells differentiation and dysfunction in chronically infected individuals. Recent longitude studies in both HCV specific- and bulk T cells reveal that chronic immune stimulation is the driving force for the impaired T cell functions, however, the underlying mechanisms remain elusive. Here, we show that peripheral CD4+ T cells from chronically HCV-infected patients exhibit lymphopenia with the reduction of naïve population and expansion of effector memory T cells. CD4+ T cells from HCV patient also display elevated activation markers. including HLA-DR, GLUT1, Granzyme B, and short-lived effector marker CD127- KLRG1+, whereas stem cell-liked transcription factor TCF1 and telomere sheterin subunit TRF2 are significant reduced, comparing to age- and gender-matched healthy controls. Mechanistically, ex vivo T cell differentiation revealed that CD4+ T cells from HCV patients exhibit PI3K/Akt/mTOR signaling hyperactivation upon TCR stimulation, favoring pro-inflammatory effector differentiation with TRF2 downregulation, rendering telomere dysfunction induced foci (TIFs) accumulation, resulting in telomeric DNA damage and cellular apoptosis. Importantly, exacerbation of telomere deprotection by knockdown of TRF2 expression in healthy T cells resulted in an increase in telomeric DNA damage and T cell apoptosis; whereas overexpression of TRF2 in HCV-T cells led to an alleviation of telomeric DNA damage and T cell death. Additionally, inhibition of Akt signaling during T cell activation can preserve precursor memory population, while limiting inflammatory effector expansion, DNA damage, and cell death. Taken together, these results suggest that modulation of immune activation by inhibiting Akt signaling and protection of telomeres by enforcing TRF2 expression could open new therapeutic strategies to balance adaptive immune responses in the setting of chronic immune activation and inflammatory in vulnerable populations such as chronically viral infected individuals.