Persecution perpetuated: The medieval origins of anti-semitic violence in Nazi Germany

How persistent are cultural traits? This paper uses data on anti-Semitism in Germany and finds continuity at the local level over more than half a millennium. When the Black Death hit Europe in 1348-50, killing between one third and one half of the population, its cause was unknown. Many contemporaries blamed the Jews. Cities all over Germany witnessed mass killings of their Jewish population. At the same time, numerous Jewish communities were spared these horrors. We use plague pogroms as an indicator for medieval anti-Semitism. Pogroms during the Black Death are a strong and robust predictor of violence against Jews in the 1920s, and of votes for the Nazi Party. In addition, cities that saw medieval anti-Semitic violence also had higher deportation rates for Jews after 1933, were more likely to see synagogues damaged or destroyed in the Night of Broken Glass in 1938, and their inhabitants wrote more anti-Jewish letters to the editor of the Nazi newspaper Der Stürmer.

IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor alpha subunit CD25.

IL-2 is crucial to T cell homeostasis, especially of CD4(+) T regulatory cells and memory CD8(+) cells, as evidenced by vigorous proliferation of these cells in vivo following injections of superagonist IL-2/anti-IL-2 antibody complexes. The mechanism of IL-2/anti-IL-2 antibody complexes is unknown owing to a lack of understanding of IL-2 homeostasis. We show that IL-2 receptor alpha (CD25) plays a crucial role in IL-2 homeostasis. Thus, prolongation of IL-2 half-life and blocking of CD25 using antibodies or CD25-deficient mice led in combination, but not alone, to vigorous IL-2-mediated T cell proliferation, similar to IL-2/anti-IL-2 antibody complexes. These data suggest an unpredicted role for CD25 in IL-2 homeostasis.

Natural killer cell receptor-repertoire and functions after induction therapy by polyclonal rabbit anti-thymocyte globulin in unsensitized kidney transplant recipients.

Polyclonal rabbit anti-thymocyte globulin (rATG) is widely used in solid organ transplantation (SOT) as induction therapy or to treat corticosteroid-resistant rejection. In vivo, the effect of rATG on natural killer (NK) cells has not been studied. These cells are of particular relevance after SOT because classical immunosuppressive drugs do not inhibit or even can activate NK cells. A cohort of 20 recipients at low immunological risk, that had been receiving rATG as induction therapy, was analyzed for receptor repertoire, cytotoxicity and capacity of NK cells to secrete IFN-γ before kidney transplantation and at different time points thereafter. NK cells expressed fewer killer-cell immunoglobulin-like receptors (KIR), fewer activating receptors NKG2D, but more inhibitory receptor NKG2A compatible with an immature phenotype in the first 6 months post transplantation. Both cytotoxicity of NK cells and the secretion of IFN-γ were preserved over time after transplantation.

Non steroidal anti-inflammatory drugs and COX-2 inhibitors as anti-cancer therapeutics: hypes, hopes and reality.

Non-steroidal anti-inflammatory drugs (NSAIDs) and specific inhibitors of cyclooxygenase (COX)-2, are therapeutic groups widely used for the treatment of pain, inflammation and fever. There is growing experimental and clinical evidence indicating NSAIDs and COX-2 inhibitors also have anti-cancer activity. Epidemiological studies have shown that regular use of Aspirin and other NSAIDs reduces the risk of developing cancer, in particular of the colon. Molecular pathology studies have revealed that COX-2 is expressed by cancer cells and cells of the tumor stroma during tumor progression and in response to chemotherapy or radiotherapy. Experimental studies have demonstrated that COX-2 over expression promotes tumorigenesis, and that NSAIDs and COX-2 inhibitors suppress tumorigenesis and tumor progression. Clinical trials have shown that NSAIDs and COX-2 inhibitors suppress colon polyp formation and malignant progression in patients with familial adenomatous polyposis (FAP) syndrome. Recent advances in the understanding of the cellular and molecular mechanisms of the anti-cancer effects of NSAIDs and COX-2 inhibitors have demonstrated that these drugs target both tumor cells and the tumor vasculature. The therapeutic benefits of COX-2 inhibitors in the treatment of human cancer in combination with chemotherapy or radiotherapy are currently being tested in clinical trials. In this article we will review recent advances in the understanding of the anti-tumor mechanisms of these drugs and discuss their potential application in clinical oncology.

The economics of anti-parasite defences in animal societies

RESUME : De nombreuses espèces animales vivent en groupe. Du simple grégarisme aux colonies hautement intégrées de fourmis, la vie sociale a atteint des degrés divers de complexité. Les nombreuses interactions entre membres d'une société favorisent la transmission de parasites. Cela représente un coût potentiel de la vie sociale. Cette thèse s'intéresse aux défenses permettant de réduire le coût du parasitisme dans les colonies de fourmis ainsi qu'à la manière dont le parasitisme a pu façonner certains aspects de ces sociétés. Les colonies de fourmis des bois (Forimica paralugubris) contiennent de grandes quantités de résine de conifères. Cette résine réduit la densité microbienne dans le nid et augmente la survie des ouvrières lors d'infections parasitaires. Dans cette thèse, nous montrons, d'une part, que les ouvrières collectent activement la résine et que ce comportement est plutôt préventif que curatif et, d'autre part, que la résine permet aux ouvrières une utilisation moindre de leurs défenses immunitaires. Ces résultats permettent de conclure que ce comportement réduit l'exposition au parasitisme et qu'il a une fonction adaptative. L'émergence d'un tel comportement de médication chez une espèce d'insectes sociaux illustre le fait que la socialité, bien yue provoquant une exposition accrue au parasitisme, permet également l'émergence de mécanismes sociaux de défense. II a été suggéré que la présence de plusieurs reines au sein d'un même nid (polygynie) améliore la résistance aux parasites en augmentant la diversité génétique au sein de la colonie. En accord avec cette hypothèse, nous montrons qu'une augmentation de la diversité génétique au sein de groupes expérimentaux de Formica selysi améliore leur survie lors d'une infection parasitaire. Cependant, nous suggérons également que sur le terrain, d'autres facteurs corrélés à la polygynie ont des effets antagoniques sur la résistance. Nous montrons par exemple que les ouvrières polygynes semblent avoir une capacité moindre à monter une réponse immunitaire. Certains aspects de la reproduction des fourmis ont pu également être façonnés par le parasitisme. L'accouplement n'a lieu que lors d'une courte période au début de la vie adulte, généralement à l'extérieur de la colonie. Les reines stockent ensuite le sperme et l'utilisent parcimonieusement au cours de leur vie alors que les males meurent rapidement. Nous montrons que les défenses immunitaires des reines de fourmis des bois (F. paralugubris) sont fortement affectées par l'accouplement. Ces modulations immunitaires sont probablement liées à une augmentation de l'exposition au parasitisme lors de l'accouplement ainsi qu'à des blessures copulatoires. I1 semble donc que l'accouplement soit accompagné de coûts immunitaires pour les reines. Dans son ensemble, cette thèse illustre la diversité des mécanismes de défenses contre les parasites dans les sociétés de fourmis. La vie sociale, en offrant un nouveau niveau d'interaction, permet en effet l'émergence d'adaptations originales. Cela explique probablement le grand succès écologique des espèces sociales. SUMMARY : Sociality is widespread among animals and has reached variable degrees of complexity, from loose social Groups to highly integrated ant colonies. The many interactions between members of a social group promote the spread of parasites, but social life also permits the evolution of original defence mechanisms. This thesis sheds light on how ant colonies defend themselves against parasites, and on how parasitism shapes certain aspects of these societies. Wood ants nests (Formica paralugubris) contain large amounts of conifer resin which reduces the microbial density in ant nests and enhances the survival of ants challenged by some pathogens. We show that resin is actively collected by workers and that resin collection is rather a prophylactic than a curative behaviour. Moreover, we suggest that resin reduces the use of the immune defences of workers. Altogether, these results indicate that the use of resin is a collective adaptation to prevent the spread of parasites. The emergence of medication in a social insect species illustrates that sociality does not only increase the exposure to parasites but also allows the emergence of social mechanisms to counter this threat. The number of reproducing queens per colony is a variable trait in ants. It has been suggested that polygyny (the occurrence of multiple queens within a colony), by increasing the colonial genetic diversity, improves disease resistance. In line with this hypothesis, we show that in a socially polymorphic ant (Formica selysi), an experimental increase of colony genetic diversity enhances disease resistance. However, we also suggest that factors covarying with queen number variation in the field have antagonistic effects on parasite resistance. We show for instance that polygyne workers seem to have lower immune defences. Parasites may also shape some aspects of ant queen reproductive biology. Ant queens mate at the beginning of their adult life, usually outside of the colony, and store sperm for several years to fertilize eggs. Males die shortly after mating and queens never remate later in life, which drastically reduces sexual conflicts. Moreover, mating and nest founding occur away from the collective defence mechanisms of the natal colony and might be associated with an increased risk of parasitism. We show that mating affects the immune defences of wood ant queens (F. paralugubris) in multiple ways that are consistent with mating wounds and increased risk of parasitism. We suggest that mating is associated with immunity costs in ants, despite the reduced level of sexual conflicts. Altogether, my thesis illustrates the diversity of anti-parasite mechanisms in ant societies. This sheds light on how sociality, by offering a new level of interactions, allows the evolution of original adaptations, which may explain the wide ecological success of social species.

The aldosterone-mineralocorticoid receptor pathway exerts anti-inflammatory effects in endotoxin-induced uveitis.

We have previously shown that the eye is a mineralocorticoid-sensitive organ and we now question the role of mineralocorticoid receptor (MR) in ocular inflammation. The endotoxin-induced uveitis (EIU), a rat model of human intraocular inflammation, was induced by systemic administration of lipopolysaccharide (LPS). Evaluations were made 6 and 24 hours after intraocular injection of aldosterone (simultaneous to LPS injection). Three hours after onset of EIU, the MR and the glucocorticoid metabolizing enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression were down-regulated in iris/ciliary body and the corticosterone concentration was increased in aqueous humor, altering the normal MR/glucocorticoid receptor (GR) balance. At 24 hours, the GR expression was also decreased. In EIU, aldosterone reduced the intensity of clinical inflammation in a dose-dependent manner. The clinical benefit of aldosterone was abrogated in the presence of the MR antagonist (RU26752) and only partially with the GR antagonist (RU38486). Aldosterone reduced the release of inflammatory mediators (6 and 24 hours: TNF-α, IFN-γ, MIP-1α) in aqueous humor and the number of activated microglia/macrophages. Aldosterone partly prevented the uveitis-induced MR down-regulation. These results suggest that MR expression and activation in iris/ciliary body could protect the ocular structures against damages induced by EIU.

Use of forensic investigations in anti-doping

The fight against doping is mainly focused on direct detection, using analytical methods for the detection of doping agents in biological samples. However, the World Anti-Doping Code also defines doping as possession, administration or attempted administration of prohibited substances or methods, trafficking or attempted trafficking in any prohibited substance or methods. As these issues correspond to criminal investigation, a forensic approach can help assessing potential violation of these rules.In the context of a rowing competition, genetic analyses were conducted on biological samples collected in infusion apparatus, bags and tubing in order to obtain DNA profiles. As no database of athletes' DNA profiles was available, the use of information from the location detection as well as contextual information were key to determine a population of suspected athletes and to obtain reference DNA profiles for comparison.Analysis of samples from infusion systems provided 8 different DNA profiles. The comparison between these profiles and 8 reference profiles from suspected athletes could not be distinguished.This case-study is one of the first where a forensic approach was applied for anti-doping purposes. Based on this investigation, the International Rowing Federation authorities decided to ban not only the incriminated athletes, but also the coaches and officials for 2 years.

Radioimmunotherapy of human colon carcinoma by 131I-labelled monoclonal anti-CEA antibodies in a nude mouse model.

A mixture of 3 MAbs directed against 3 different CEA epitopes was radiolabelled with 131I and used for the treatment of a human colon carcinoma transplanted s.c. into nude mice. Intact MAbs and F(ab')2 fragments were mixed because it had been shown by autoradiography that these 2 antibody forms can penetrate into different areas of the tumor nodule. Ten days after transplantation of colon tumor T380 a single dose of 600 microCi of 131I MAbs was injected i.v. The tumor grafts were well established (as evidenced by exponential growth in untreated mice) and their size continued to increase up to 6 days after radiolabelled antibody injection. Tumor shrinking was then observed lasting for 4-12 weeks. In a control group injected with 600 microCi of 131I coupled to irrelevant monoclonal IgG, tumor growth was delayed, but no regression was observed. Tumors of mice injected with the corresponding amount of unlabelled antibodies grew like those of untreated mice. Based on measurements of the effective whole-body half-life of injected 131I, the mean radiation dose received by the animals was calculated to be 382 rads for the antibody group and 478 rads for the normal IgG controls. The genetically immunodeficient animals exhibited no increase in mortality, and only limited bone-marrow toxicity was observed. Direct measurement of radioactivity in mice dissected 1, 3 and 7 days after 131I-MAb injection showed that 25, 7.2 and 2.2% of injected dose were recovered per gram of tumor, the mean radiation dose delivered to the tumor being thus more than 5,000 rads. These experiments show that therapeutic doses of radioactivity can be selectively directed to human colon carcinoma by i.v. injection of 131I-labelled anti-CEA MAbs.

Use of forensic investigations in anti-doping.

The fight against doping is mainly focused on direct detection, using analytical methods for the detection of doping agents in biological samples. However, the World Anti-Doping Code also defines doping as possession, administration or attempted administration of prohibited substances or methods, trafficking or attempted trafficking in any prohibited substance or methods. As these issues correspond to criminal investigation, a forensic approach can help assessing potential violation of these rules. In the context of a rowing competition, genetic analyses were conducted on biological samples collected in infusion apparatus, bags and tubing in order to obtain DNA profiles. As no database of athletes' DNA profiles was available, the use of information from the location detection as well as contextual information were key to determine a population of suspected athletes and to obtain reference DNA profiles for comparison. Analysis of samples from infusion systems provided 8 different DNA profiles. The comparison between these profiles and 8 reference profiles from suspected athletes could not be distinguished. This case-study is one of the first where a forensic approach was applied for anti-doping purposes. Based on this investigation, the International Rowing Federation authorities decided to ban not only the incriminated athletes, but also the coaches and officials for 2 years.

In vivo targeting of an anti-tumor antibody coupled to antigenic MHC class I complexes induces specific growth inhibition and regression of established syngeneic tumor grafts.

The concept of antibody-mediated targeting of antigenic MHC/peptide complexes on tumor cells in order to sensitize them to T-lymphocyte cytotoxicity represents an attractive new immunotherapy strategy. In vitro experiments have shown that an antibody chemically conjugated or fused to monomeric MHC/peptide can be oligomerized on the surface of tumor cells, rendering them susceptible to efficient lysis by MHC-peptide restricted specific T-cell clones. However, this strategy has not yet been tested entirely in vivo in immunocompetent animals. To this aim, we took advantage of OT-1 mice which have a transgenic T-cell receptor specific for the ovalbumin (ova) immunodominant peptide (257-264) expressed in the context of the MHC class I H-2K(b). We prepared and characterized conjugates between the Fab' fragment from a high-affinity monoclonal antibody to carcinoembryonic antigen (CEA) and the H-2K(b) /ova peptide complex. First, we showed in OT-1 mice that the grafting and growth of a syngeneic colon carcinoma line transfected with CEA could be specifically inhibited by systemic injections of the conjugate. Next, using CEA transgenic C57BL/6 mice adoptively transferred with OT-1 spleen cells and immunized with ovalbumin, we demonstrated that systemic injections of the anti-CEA-H-2K(b) /ova conjugate could induce specific growth inhibition and regression of well-established, palpable subcutaneous grafts from the syngeneic CEA-transfected colon carcinoma line. These results, obtained in a well-characterized syngeneic carcinoma model, demonstrate that the antibody-MHC/peptide strategy can function in vivo. Further preclinical experimental studies, using an anti-viral T-cell response, will be performed before this new form of immunotherapy can be considered for clinical use.

Iodine-131-labeled MAb F(ab')2 fragments are more efficient and less toxic than intact anti-CEA antibodies in radioimmunotherapy of large human colon carcinoma grafted in nude mice.

During one week, beginning 18 days after transplantation, nude mice bearing human colon carcinoma ranging from 115 to 943 mm3 (mean 335 mm3) were treated by repeated intravenous injections of either iodine-131-(131I) labeled intact antibodies or 131I-labeled corresponding F(ab')2 fragments of a pool of four monoclonal antibodies (MAbs) directed against distinct epitopes of carcinoembryonic antigen (CEA). Complete tumor remission was observed in 8 of 10 mice after therapy with F(ab')2 and 6 of the animals survived 10 mo in good health. In contrast, after treatment with intact MAbs, tumors relapsed in 7 of 8 mice after remission periods of 1 to 3.5 mo despite the fact that body weight loss and depression of peripheral white blood cells, symptoms of radiation toxicity, and the calculated radiation doses for liver, spleen, bone, and blood were increased or equal in these animals as compared to mice treated with F(ab')2.

Anti-60kDa heat shock protein antibodies in fetal serum : a biomarker for unexplained small for gestational age fetuses

Rapport de synthèseObjectifsLe retard de croissance intrautérin (RCIU) est un problème affectant 10% des grossesses et est associé à une morbidité périnatale importante. Dans environ 80% des cas, une étiologie ou un facteur de risque majeur peuvent être identifiés. Mais près de 20% des cas sont considérés comme inexpliqués. La heat shock protéine 60kDa (HSP60) est une protéine fortement immunogène dont la synthèse est considérablement augmentée lors de conditions non- physiologiques. Les HSP60 humaines et bactériennes partagent un haut degré d'homologie de séquence ce qui peut engendrer une maladie auto-immune à la suite d'une infection bactérienne. Nous avons supposé que les RCIU inexpliqués pourraient être la conséquence d'une sensibilisation à l'HSP60 humaine.MéthodesLes RCIU inexpliqués ont été identifiés par mesure échographique avec un doppler normal, sans anomalies décelables chez la mère ou le foetus. Les sera foetaux ont été obtenus par cordocentèse, effectuée lors d'analyse du caryotype en cas de RCIU inexpliqué (groupe d'étude) ou pour le dépistage d'une incompatibilité Rhésus (groupe témoin). Ils ont été testés pour l'antigène HSP60 et les IgG et IgM anti-HSP60 par ELISA ainsi que pour d'autres paramètres immunitaires et hématologiques.RésultatsLes paramètres maternels sont similaires entre les 12 cas du groupe d'étude et les 23 cas du groupe contrôle. L'âge gestationnel moyen lors de la cordocentèse est de 29 semaines. Les IgM anti-HSP60 sont détectés dans 12 cas d'étude (100%) mais dans aucun cas contrôle (p <0,00017), les IgG anti-HSP60 dans 7 cas d'étude (58%) et un seul dans le groupe contrôle (p <0,001). Trois des quatre cas avec les taux d'IgM les plus élevés sont décédés. Il n'y a pas de différences entre les deux groupes quant aux taux d'antigène HSP60 ou d'autres marqueurs immunologiques ou hématologiques.ConclusionLes foetus avec un RCIU inexpliqué expriment un taux élevé d'anticorps IgM et IgG contre l'HSP60 humaine et le taux d'IgM est un facteur prédictif de la mortalité foetale. La détection de ces anticorps indique qu'une perturbation placentaire et une réaction auto-immune foetale liée à l'HSP60 sont associées à ce retard de développement chez le foetus.

Systematic Assessment of Factors Influencing Preferences of Crohn's Disease Patients in Selecting an Anti-TNF agent (CHOOSE TNF TRIAL)

Background a nd A ims: I nfliximab (IFX), adalimumab (ADA)and certolizumab pegol (CZP) have similar efficacy for inductionand maintenance of clinical response and remission in Crohn'sdisease (CD). Given the comparable nature of t hese drugs,patients' p references m ay i nfluence the choice o f the product.Goal: to identify factors contributing to CD patients' decision inselecting one anti-TNF agent over the others.Methods: A p rospectdive s urvey was performed a mong a nti-TNF-naïve CD patients. Prior to completion of a questionnaire,patients were provided with a description of the three anti-TNFagents f ocusing on indications, route of administration, s ideeffects, and scientific evidence of efficacy and safety.Results: One hundred patients (47f/53m, mean age 45±16yrs)completed the questionnaire. Disease location was ileal, colonicand ileocolonic in 33%, 40% and 27% of patients, respectively.Thirty-six percent preferred ADA as medication of choice, while28% and 2 5% p referred CZP and IFX; 11% were u ndecided.Patients' decision in selecting an anti-TNF drug was influencedby t he following f actors: side effects ( 76%), p hysician'srecommendation (66%), route of administration (54%), efficacydata (52%), time required for therapy administration (27%),recommendations by other CD patients (21%) and interactionswith other medications (12%).Conclusions: T he majority of p atients p referred anti-TNFmedications t hat were a dministered by s ubcutaneous i njectionrather t han b y intravenous i nfusion. Side effect profile andphysicians' r ecommendation are t wo m ajor factors influencingthe patients' s election of a specific anti-TNF d rug. Patients'concerns about safety and lifestyle habits should be taken intoaccount when prescribing anti-TNF drugs.

Expression of apoptosis and survival genes in human memory T cell populations

RESUME Introduction: Les cellules T mémoires humaines sont classées en trois sous-populations sur la base de l'expression d'un marqueur de surface cellulaire, CD45RA, et du récepteur aux chimiokines, CCR7. Ces sous-populations, nommées cellules mémoires centrales (TcM), mémoires effectrices (TEM) et mémoires effectrices terminales (ITEM), ont des rôles fonctionnels distincts, ainsi que des capacités de prolifération et de régénération différentes. Cependant, la génération de ces différences reste encore mal comprise et on ignore les mécanismes moléculaires impliqués. Matériaux et Méthodes: Des cellules mononucléaires humaines du sang périphérique ont été séparées par cytométrie de flux selon leur expression de CD4, CD8, CD45RA et CCR7 en sous-populations de cellules CD4+ ou CD8+ naïves, TcM, TEM ou ITEM. Dans chacune de ces sous-populations, 14 gènes impliqués dans l'apoptose, la survie ou la capacité proliférative des cellules T ont été quantifiés par RT-PCR en temps réel, relativement à l'expression d'un gène de référence endogène. L'ARN provenant de 450 cellules T a été utilisé par gène et par sous-population. Les gènes analysés (cibles) comprenaient des gènes de survie (BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα, IL-7Rα), des gènes anti-apoptotiques (Bcl-2, BclxL, FLIP), des gènes pro-apoptotiques (Bad, Bax, Fast) et le gène anti-prolifératif, Tob. A l'aide de la méthode comparative delta-delta-CT, le taux d'expression des gènes cibles de chaque sous-population des cellules T mémoires CD4+ et CD8+, à été comparée à leur taux d'expression dans les cellules T naïves CD4+ et CD8+. Résultats: Dans les cellules CD8+, les gènes pro-apoptotiques Bax et Fast étaient surexprimés dans toutes les sous-populations mémoires, tandis que l'expression des facteurs anti-apoptotiques et de survie comme Bcl-2, APRIL et BAFF-R, étaient diminués. Ces deux tendances étaient particulièrement accentuées dans les sous-groupes des cellules mémoires TEM et TTEM. A noter que malgré le fait que leur expression était également diminuée dans les autres cellules mémoires, le facteur de survie IL-7Ra, était sélectivement surexprimé dans la sous-population de cellules TcM et l'expression d'IL-15Ra était sélectivement augmentée dans les TEM. Dans les cellules CD4+, le taux d'expression des gènes analysés était plus variable entre les sujets étudiés que dans les cellules CD8+, ne permettant pas de définir un profil d'expression spécifique. L'expression du gène de survie BAFF par contre, a été significativement augmentée dans toutes les sous-populations mémoire CD4+. Il en va de même pour l'expression d' APRIL et de BAFF-R, bien que dans moindre degré. A remarquer que l'expression du facteur anti-apoptotique Fast a été observée uniquement dans la souspopulation des TTEM. Discussion et Conclusions: Cette étude montre une nette différence entre les cellules CD8+ et CD4+, en ce qui concerne les profils d'expression des gènes impliqués dans la survie et l'apoptose des cellules T mémoires. Ceci pourrait impliquer une régulation cellulaire homéostatique distincte dans ces deux compartiments de cellules T mémoires. Dans les cellules CD8+ l'expression d'un nombre de gènes impliqués dans la survie et la protection de l'apoptose semblerait être diminuée dans les populations TEM et TTEM en comparaison à celle des sous-populations naïves et TEM, tandis que l'expression des gènes pro-apoptotiques semblerait être augmentée. Comme ceci paraît être plus accentué dans les TTEM, cela pourrait indiquer une plus grande disposition à l'apopotose dans les populations CCR7- (effectrices) et une perte de survie parallèlement à l'acquisition de capacités effectrices. Ceci parlerait en faveur d'un modèle de différentiation linéaire dans les cellules CD8+. De plus, l'augmentation sélective de l'expression d'IL-7Ra observée dans le sous-groupe de cellules mémoires TEM, et d'IL-15Ra dans celui des TEM, pourrait indiquer un moyen de sélection pour des réponses immunitaires mémoires à long terme par une réponse distincte à ces cytokines. Dans les cellules CD4+ par contre, aucun profil d'expression n'a pu être déterminé; les résultats suggèrent même une résistance relative à l'apoptose de la part des cellules mémoires. Ceci pourrait favoriser l'existence d'un modèle de différentiation plus flexible avec des possibilités d'interaction multiples. Ainsi, la surexpression sélective de BAFF, APRIL et BAFF-R dans les sous-populations individuelles des cellules mémoires pourrait être un indice de l'interaction de ces sous-groupes avec des cellules B. ABSTRACT Introduction: Based on their surface expression of the CD45 isoform and of the CCR7 chemokine receptor, memory T cells have been divided into the following three subsets: central memory (TAM), effector memory (TEM) and terminal effector memory (ITEM). Distinct functional roles and different proliferative and regenerative capacities have been attributed to each one of these subpopulations. The molecular mechanisms underlying these differences; however, remain poorly understood. Materials and Methods: According to their expression of CD4, CD8, CD45RA and CCR7, human peripheral blood mononuclear cells were sorted by flow-cytometry into CD4+ or CD8+ naïve, TAM, TEM and ITEM subsets. Using real-time PCR, the expression of 14 genes known to be involved in apoptotis, survival or proliferation of T cells was quantified separately in each individual subset, relative to an endogenous reference gene. The RNA equivalent of 450 T cells was used for each gene and subset. The target gene panel included the survival genes BAFF, APRIL, BAFF-R, BCMA, TACI, IL-15Rα and IL-7Rα, the anti-apoptotic genes Bcl2, Bcl-xL and FLIP, the pro-apoptotic genes Bad, Bax and Fast, as well as the antiproliferative gene Tob. Using the comparative CT-method, the expression of the target genes in the three memory T cell subsets of both CD4+ and CD8+ T cell populations was compared to their expression in the naïve T cells. Results: In CD8+ cells, the pro-apoptotic factors Bax and Fast were found to be upregulated in all memory T cell subsets, whereas the survival and anti-apoptotic factors Bcl-2, APRIL and BAFF-R were downregulated. These tendencies were most accentuated in TEM and TTEM subsets. Even though the survival factor IL-7Rα was also downregulated in these subsets, interestingly, it was selectively upregulated in the CD8+ TAM subset. Similarly, IL-15Rαexpression was shown to be selectively upregulated in the CD8+ TEM subset. In CD4+ cells, the expression levels of the analyzed genes showed a greater inter-individual variability than in CD8+ cells, thus suggesting the absence of any particular expression pattern for CD4+ memory T cells. However, the survival factor BAFF was found to be significantly upregulated in all CD4+ memory T cell subsets, as was also the expression of APRIL and BAFF-R, although to a lesser extent. Furthermore, it was noted that the pro-apoptotic gene Fast was only expressed in the TTEM CD4+ subset. Discussion and Conclusions: Genes involved in apoptosis and survival in human memory T cells have been shown to be expressed differently in CD8+ cells as compared to CD4+ cells, suggesting a distinct regulation of cell homeostasis in these two memory T cell compartments. The present study suggests that, in CD8+ T cells, the expression of various survival and antiapoptotic genes is downregulated in TEM and TTEM subsets, while the expression of proapoptotic genes is upregulated in comparison to the naïve and the TAM populations. These characteristics, potentially translating to a greater susceptibility to apoptosis in the CCR7- (effector) memory populations, are accentuated in the TTEM population, suggesting a loss of survival in parallel to the acquisition of effector capacities. This speaks in favour of a linear differentiation model in CD8+ T memory cells. Moreover, the observed selectively increased expression of IL-7Rα in CD8+ TAM cells - as that of IL-15Rα in CD8+ TEM cells -suggest that differential responsiveness to cytokines could confer a selection bias for distinct long-term memory cell responses. Relative to the results for CD8+ T cells, those for CD4+ T cells seem to indicate a certain resistance of the memory subsets to apoptosis, suggesting the possibility of a more flexible differentiation model with multiple checkpoints and potential interaction of CD4+ memory cells with other cells. Thus, the selective upregulation of BAFF, APRIL and BAFF-R in individual memory subsets could imply an interaction of these subsets with B cells.