Phenotypic heterogeneity of antigen-specific CD4 cells under different conditions of antigen persistence and antigen load

RESUME Nous n'avons pas de connaissance précise des facteurs à l'origine de l'hétérogénéité phénotypique des cellules T CD4 mémoires. Une troisième population phénotypique des cellules T CD4 mémoires, caractérisée par les marqueurs CD45RA+CCR7- a été identifiée dans cette étude. Cette population présente un état de différentiation avancée, comme en témoigne son histoire de réplication, ainsi que sa capacité de prolifération homéostatique. Les réponses des cellules T CD4 mémoires à différentes conditions de persistance et charge antigénique ont trois patterns phénotypiques différents, caractérisés par les marqueurs CD45RA et CCR7. La réponse CD4 mono -phénotypique CD45RA-CCR7+ ou CD45RA- CCR7- est associée à des conditions d'élimination de l'antigène (telle la réponse CD4 tétanos spécifique) ou à des conditions de persistance antigénique et de virémie élevée (telle la réponse HIV chronique ou la primo-infection CMV) respectivement. D'autre part, les réponses T CD4 multi -phénotypiques CD45RA-CCR7+ sont associées à des conditions d'exposition antigénique prolongée et de faible virémie (telles les infections CMV, EBV et HSV ou les infections HIV chez les long term non progressons). La réponse mono -phénotypique CD45RA- CCR7+ est propre aux cellules T CD4 secrétant de IL2, définies également comme centrales mémoires, la réponse CD45RA- CCR7- aux cellules T CD4 secrétant de l'IFNγ et finalement la réponse mufti-phénotypique aux cellules T CD4 secrétant à la fois de l'IL2 et de l' IFNγ. En conclusion, ces résultats témoignent d'une régulation de l'hétérogénéité phénotypique par l'exposition et la charge antigénique. ABSTRACT The factors responsible for the phenotypic heterogeneity of memory CD4 T cells are unclear. In the present study, we have identified a third population of memory CD4 T cells characterized as CD45RA+CCRT that, based on its replication history and the homeostatic proliferative capacity, was at an advanced stage of differentiation. Three different phenotypic patterns of memory CD4 T cell responses were delineated under different conditions of antigen (Ag) persistence and load using CD45RA and CCR7 as markers of memory T cells. Mono-phenotypic CD45RA'CCR7+ or CD45RA'CCR7' CD4 T cell responses were associated with conditions of Ag clearance (tetanus toxoid-specific CD4 T cell response) or Ag persistence and high load (chronic HIV-1 and primary CMV infections), respectively. Multi-phenotypic CD45RA CCR7+, CD45RA'CCRT and CD45RA+CCRT CD4 T cell responses were associated with protracted Ag exposure and low load (chronic CMV, EBV and HSV infections and HIV-1 infection in long-term nonprogressors). The mono-phenotypic CD45RA'CCR7+ response was typical of central memory (TCM) IL-2-secreting CD4 T cells, the mono-phenotypic CD45RA CCRT response of effector memory (TEM) IFN-γ -secreting CD4 T cells and the multi-phenotypic response of both IL-2- and IFN-γ -secreting cells. The present results indicate that the heterogeneity of different Ag-specific CD4 T cell responses is regulated by Ag exposure and Ag load.

HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

Background: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. <p>Objective: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. Methods: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. Results: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/mu l; P= 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (Cl) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7(95%Cl, 1.2-11.3) and 5.9 (95% Cl, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log(10)copies/ml, respectively, compared with < 2.2 log(10)copies/ml. Conclusions: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Phenotypic heterogeneity of antigen-specific CD4 T cells under different conditions of antigen persistence and antigen load.

The factors responsible for the phenotypic heterogeneity of memory CD4 T cells are unclear. In the present study, we have identified a third population of memory CD4 T cells characterized as CD45RA(+)CCR7(-) that, based on its replication history and the homeostatic proliferative capacity, was at an advanced stage of differentiation. Three different phenotypic patterns of memory CD4 T cell responses were delineated under different conditions of antigen (Ag) persistence and load using CD45RA and CCR7 as markers of memory T cells. Mono-phenotypic CD45RA(-)CCR7(+) or CD45RA(-)CCR7(-) CD4 T cell responses were associated with conditions of Ag clearance (tetanus toxoid-specific CD4 T cell response) or Ag persistence and high load (chronic HIV-1 and primary CMV infections), respectively. Multi-phenotypic CD45RA(-)CCR7(+), CD45RA(-)CCR7(-) and CD45RA(+)CCR7(-) CD4 T cell responses were associated with protracted Ag exposure and low load (chronic CMV, EBV and HSV infections and HIV-1 infection in long-term nonprogressors). The mono-phenotypic CD45RA(-)CCR7(+) response was typical of central memory (T(CM)) IL-2-secreting CD4 T cells, the mono-phenotypic CD45RA(-)CCR7(-) response of effector memory (T(EM)) IFN-gamma-secreting CD4 T cells and the multi-phenotypic response of both IL-2- and IFN-gamma-secreting cells. The present results indicate that the heterogeneity of different Ag-specific CD4 T cell responses is regulated by Ag exposure and Ag load.

Quantitative real-time polymerase chain reaction for detection of adenovirus after T cell-replete hematopoietic cell transplantation: viral load as a marker for invasive disease.

BACKGROUND: The value of adenovirus plasma DNA detection as an indicator for adenovirus disease is unknown in the context of T cell-replete hematopoietic cell transplantation, of which adenovirus disease is an uncommon but serious complication. METHODS: Three groups of 62 T cell-replete hematopoietic cell transplant recipients were selected and tested for adenovirus in plasma by polymerase chain reaction. RESULTS: Adenovirus was detected in 21 (87.5%) of 24 patients with proven adenovirus disease (group 1), in 4 (21%) of 19 patients who shed adenovirus (group 2), and in 1 (10.5%) of 19 uninfected control patients. The maximum viral load was significantly higher in group 1 (median maximum viral load, 6.3x10(6) copies/mL; range, 0 to 1.0x10(9) copies/mL) than in group 2 (median maximum viral load, 0 copies/mL; range, 0 to 1.7x10(8) copies/mL; P<.001) and in group 3 (median maximum viral load, 0 copies/mL; range 0-40 copies/mL; P<.001). All patients in group 2 who developed adenoviremia had symptoms compatible with adenovirus disease (i.e., possible disease). A minimal plasma viral load of 10(3) copies/mL was detected in all patients with proven or possible disease. Adenoviremia was detectable at a median of 19.5 days (range, 8-48 days) and 24 days (range, 9-41 days) before death for patients with proven and possible adenovirus disease, respectively. CONCLUSION: Sustained or high-level adenoviremia appears to be a specific and sensitive indicator of adenovirus disease after T cell-replete hematopoietic cell transplantation. In the context of low prevalence of adenovirus disease, the use of polymerase chain reaction of plasma specimens to detect virus might be a valuable tool to identify and treat patients at risk for viral invasive disease.

Exploration of immune competencies of viral-specific CD8+T cells in MS patients using tetramers and functional CTL assays

Introduction: Epstein-Barr Virus(EBV) has been repeatedly associatedwith multiple sclerosis (MS). Wehave previously shown that there is ahigh peripheral as well as intrathecalactivation of EBV-, but not cytomegalovirus(CMV)-specific CD8+ Tcells, early in the course of MS,strengthening the link between EBVand MS. However, the trigger of thisincreased EBV-specific CD8+ T cellresponse remains obscure. It could resultfrom a higher EBV viral load. Alternatively,it could be due to an intrinsicallydeficient EBV-specificCTL response, cytotoxic granulesmediated.Thus, we performed anin-depth study of the phenotype of exvivo EBV- and CMV-specific CD8+T cells in MS patients and control patients,assessing their cytotoxic activity.Methods:We analyzed the profileof cytotoxic granules in EBV- andCMV-specific CD8+ T cells in a cohortof 13 early MS patients, 20 lateMS, 30 other neurological diseases(OND) patients and 7 healthy controlsubjects. Ex vivo analysis of EBV- orCMV-specific CD8+ T cells was performedusing HLA class I/tetramercomplexes coupled to CCR7 andCD57 markers in conjunction withperforin, granzymes A, BandKstaining.In a sub-cohort of MS patientsand controls, cytotoxic activity ofEBV- and CMV-specific CD8+ Tcells was investigated using a functionalCFSE CTL assay. Results: UsingHLA Class I tetramers for EBVand CMV, we found that the frequencyof EBV- or CMV-specificCD8+ T cells were similar in all studysubjects. Most of EBV- and CMVspecificCD8+Tcells were highly differentiated(CCR7-) and a variousproportion expressed the exhaustionmarker CD57. MS and OND patientshad increased perforin expression inEBV-specific CD8+ T cells. Most importantly,we found that MS patientswith longer disease duration tended tohave lower CTL cytotoxicity as comparedto earlyMSpatients or controls.Conclusions: Effector EBV-specificCD8+ T cells are increased in earlyMS, however their cytotoxic granuleprofile does not seem to be fully alteredand the cytotoxic activity ofthese cells is normal. However, thecytotoxic activity of CTL decreasedin late MS patients suggesting an exhaustionof EBV-specific CD8+ Tcells possibly due to EBV reactivation.This work was supported by theSwiss National Foundation PP00B3-124893, the Swiss Society for MS,and the Biaggi Foundation to RADP.

Polyfunctional HCV-specific T-cell responses are associated with effective control of HCV replication.

HCV infection has a severe course of disease in HIV/HCV co-infection and in liver transplant recipients. However, the mechanisms involved remain unclear. Here, we evaluated functional profiles of HCV-specific T-cell responses in 86 HCV mono-infected patients, 48 HIV/HCV co-infected patients and 42 liver transplant recipients. IFN-gamma and IL-2 production and ability of CD4 and CD8 T cells to proliferate were assessed after stimulation with HCV-derived peptides. We observed that HCV-specific T-cell responses were polyfunctional in HCV mono-infected patients, with presence of proliferating single IL-2-, dual IL-2/IFN-gamma and single IFN-gamma-producing CD4+ and dual IL-2/IFN-gamma and single IFN-gamma-producing CD8+ cells. In contrast, HCV-specific T-cell responses had an effector profile in HIV/HCV co-infected individuals and liver transplant recipients with absence of single IL-2-producing HCV-specific CD4+ and dual IL-2/IFN-gamma-producing CD8+ T cells. In addition, HCV-specific proliferation of CD4+ and CD8+ T cells was severely impaired in HIV/HCV co-infected patients and liver transplant recipients. Importantly, "only effector" T-cell responses were associated with significantly higher HCV viral load and more severe liver fibrosis scores. Therefore, the present results suggest that immune-based mechanisms may contribute to explain the accelerated course of HCV infection in conditions of HIV-1 co-infection and liver transplantation.

A new electrophysiological index for working memory load in humans.

Working memory, the ability to store and simultaneously manipulate information, is affected in several neuropsychiatric disorders which lead to severe cognitive and functional deficits. An electrophysiological marker for this process could help identify early cerebral function abnormalities. In subjects performing working memory-specific n-back tasks, event-related potential analysis revealed a positive-negative waveform (PNwm) component modulated in amplitude by working memory load. It occurs in the expected time range for this process, 140-280 ms after stimulus onset, superimposed on the classical P200 and N200 components. Independent Component Analysis extracted two functional components with latencies and topographical scalp distributions similar to the PNwm. Our results imply that the PNwm represents a new electrophysiological index for working memory load in humans.

Modulation of TCR avidity of primary HIV-1-specific CD8 T-cell responses by early and potent antiviral therapy responses

Background: CD8 T-cells play a critical role in antiviral immunity. However, mechanisms of virus control and immune correlates of protection are still not fully understood. Among other factors, TCR avidity (antigen sensitivity) is thought to play a critical role. Whereas there is a large consensus that high TCR avidity T-cell responses are correlated to higher efficacy against cancer and acute viral infections, it may be not the case in chronic persistent viral infections. Methods: TCR avidity (measured by the effect concentration 50% [EC50]) of HIV-1-specific CD8 T-cell responses directed against optimal epitopes was investigated in different cohorts of HIV-1- infected subjects (n¼114) including early acute and chronic (progressive and non-progressive) HIV-1-infection. Overall, TCR avidity was investigated in 245 HIV-1-specific CD8 T-cell responses. The relationships between TCR avidity, T-cell differentiation and functional profile including cytokine secretion, proliferation and cytotoxic potential (determined by polychromatic flow cytometry) were analyzed. Results: HIV-1-specific CD8 T-cell responses from patients with acute infection had significantly lower TCR avidity as compared to patients with chronic (progressive or non-progressive) HIVinfection (P¼0.03 and 0.003, respectively). These differences remained significant when the analyses were restricted to common epitopes (same epitopes restricted by the same class I HLA). Interestingly, some patients treated during acute infection underwent spontaneous treatment interruption. Re-exposure to high viral load induced two major effects: a) the increase in TCR avidity of pre-existing high avidity (EC50<0.01) T-cell responses (P<0.02) and b) the generation of new T-cell responses with higher TCR avidity as compared to the average pre-existing T-cell responses. Conclusion: These results suggest that high TCR avidity T-cell responses are selected during the course of HIV-1 infection and that one of the potential driving mechanisms is continuous exposure to HIV-1 antigens. These results advance our understanding of the relationship between TCR avidity and Ag exposure of antiviral memory CD8 T-cells.

Lymphodepletion by short-term chemotherapy does not alter the highly stable and persistent EBV specific CD8 T cell repertoire

Protective T cell responses againstpersistent viruses like Epstein-Barrvirus in healthy individuals are characterizedby a remarkable stability ofthe T cell receptor (TCR) clonotypicrepertoire, with highly preservedclonotype selection and persistenceover time. Here, we extended recentwork to the study of EBV-specificCD8 T cell responses in melanomapatients treated by short-term chemotherapyfor transient lymphodepletion,followed by adoptive cell transfer(ACT) and immune reconstitutionfor cancer therapy. After this treatment,we observed increased proportionsof virus-specific T cells in 3/5patients, accompanied by a more differentiatedphenotype (EMRA/CD28neg), compared to specific cells ofhealthy individuals. Yet, similarly tohealthy donors, clonotype selectionand composition of virus-specific Tcells varied along the pathway of celldifferentiation, with some clonotypesthat were selected with late differentiation,while others were not. Aftertreatment, we did not observe noveldominant clonotypes, likely related toabsence of EBV reactivation measuredas viral load levels by quantitativePCR in PBMCs and antibody levelsin plasma samples. Furthermore,public TCR BV signatures were frequentlyfound within T cell clonotypesthat dominated the repertoiresof patients, in line with those observedin healthy individuals. Ourfindings indicate that even in situationswhere the immune system isstrongly challenged such as followinglymphodepletion and homeostatic repopulation,cytotoxic T cells specificfor EBV remain strikingly stable interms of clonotype selection and com-position along T cell differentiation.We are currently characterizing theclonotype selection and gene expressionprofiles of single EBV-specificCD8 T lymphocytes sorted ex-vivo inone patient who underwent two cyclesof lymphodepletion with escaladingdoses of chemotherapy overone-year interval. Observations madefrom this setting will provide additionalinsight into the degree of stabilityof virus specific T cells, and changesin the expression levels of genesimportant for cytolytic function andlong-term survival of T cells. Thiswork is supported by the Swiss NationalCenter of Competence in Research(NCCR) Molecular Oncology,and the Swiss National Science Foundation.

Heterozygosity-fitness correlations among wild populations of European tree frogs (Hyla arborea) detect fixation load.

Quantifying the impacts of inbreeding and genetic drift on fitness traits in fragmented populations is becoming a major goal in conservation biology. Such impacts occur at different levels and involve different sets of loci. Genetic drift randomly fixes slightly deleterious alleles leading to different fixation load among populations. By contrast, inbreeding depression arises from highly deleterious alleles in segregation within a population and creates variation among individuals. A popular approach is to measure correlations between molecular variation and phenotypic performances. This approach has been mainly used at the individual level to detect inbreeding depression within populations and sometimes at the population level but without consideration about the genetic processes measured. For the first time, we used in this study a molecular approach considering both the interpopulation and intrapopulation level to discriminate the relative importance of inbreeding depression vs. fixation load in isolated and non-fragmented populations of European tree frog (Hyla arborea), complemented with interpopulational crosses. We demonstrated that the positive correlations observed between genetic heterozygosity and larval performances on merged data were mainly caused by co-variations in genetic diversity and fixation load among populations rather than by inbreeding depression and segregating deleterious alleles within populations. Such a method is highly relevant in a conservation perspective because, depending on how populations lose fitness (inbreeding vs. fixation load), specific management actions may be designed to improve the persistence of populations.

Surface deterioration of dental materials after simulated toothbrushing in relation to brushing time and load.

OBJECTIVES: (1) To evaluate the changes in surface roughness and gloss after simulated toothbrushing of 9 composite materials and 2 ceramic materials in relation to brushing time and load in vitro; (2) to assess the relationship between surface gloss and surface roughness. METHODS: Eight flat specimens of composite materials (microfilled: Adoro, Filtek Supreme, Heliomolar; microhybrid: Four Seasons, Tetric EvoCeram; hybrid: Compoglass F, Targis, Tetric Ceram; macrohybrid: Grandio), two ceramic materials (IPS d.SIGN and IPS Empress polished) were fabricated according to the manufacturer's instructions and optimally polished with up to 4000 grit SiC. The specimens were subjected to a toothbrushing (TB) simulation device (Willytec) with rotating movements, toothpaste slurry and at three different loads (100g/250g/350g). At hourly intervals from 1h to 10h TB, mean surface roughness Ra was measured with an optical sensor and the surface gloss (Gl) with a glossmeter. Statistical analysis was performed for log-transformed Ra data applying two-way ANOVA to evaluate the interaction between load and material and load and brushing time. RESULTS: There was a significant interaction between material and load as well as between load and brushing time (p<0.0001). The microhybrid and hybrid materials demonstrated more surface deterioration with higher loads, whereas with the microfilled resins Heliomolar and Adoro it was vice versa. For ceramic materials, no or little deterioration was observed over time and independent of the load. The ceramic materials and 3 of the composite materials (roughness) showed no further deterioration after 5h of toothbrushing. Mean surface gloss was the parameter which discriminated best between the materials, followed by mean surface roughness Ra. There was a strong correlation between surface gloss and surface roughness for all the materials except the ceramics. The evaluation of the deterioration curves of individual specimens revealed a more or less synchronous course suspecting hinting specific external conditions and not showing the true variability in relation to the tested material. SIGNIFICANCE: The surface roughness and gloss of dental materials changes with brushing time and load and thus results in different material rankings. Apart from Grandio, the hybrid composite resins were more prone to surface changes than microfilled composites. The deterioration potential of a composite material can be quickly assessed by measuring surface gloss. For this purpose, a brushing time of 10h (=72,000 strokes) is needed. In further comparative studies, specimens of different materials should be tested in one series to estimate the true variability.

Bystander-Activated Memory CD8 T Cells Control Early Pathogen Load in an Innate-like, NKG2D-Dependent Manner.

During an infection the antigen-nonspecific memory CD8 T cell compartment is not simply an inert pool of cells, but becomes activated and cytotoxic. It is unknown how these cells contribute to the clearance of an infection. We measured the strength of T cell receptor (TCR) signals that bystander-activated, cytotoxic CD8 T cells (BA-CTLs) receive in vivo and found evidence of limited TCR signaling. Given this marginal contribution of the TCR, we asked how BA-CTLs identify infected target cells. We show that target cells express NKG2D ligands following bacterial infection and demonstrate that BA-CTLs directly eliminate these target cells in an innate-like, NKG2D-dependent manner. Selective inhibition of BA-CTL-mediated killing led to a significant defect in pathogen clearance. Together, these data suggest an innate role for memory CD8 T cells in the early immune response before the onset of a de novo generated, antigen-specific CD8 T cell response.

Evaluation of the specific IgG- and IgA-antibody response against immundominant Aspergillus fumigatus antigens as diagnostic markers of invasive aspergillosis

An improvement in the serological diagnostic toolbox of invasive aspergillosis (IA) is necessary. So far, most laboratories do not perform antibody detection assays at all to diagnose IA, as commercial test systems are based on crude and undefined antigen mixtures of A. fumigatus. Utilizing the A. fumigatus protein mitogillin, we could demonstrate that the use of selected characterized immunodominant antigens can improve the serodiagnosis of Aspergillus-related diseases. In an animal model we were able to identify additional 36 immunodominant antigens of a cDNA library of A. fumigatus germlings. Five selected antigens were expressed recombinantly in E. coli, purified and used for Westernblot und ELISA analyses to study the kinetics of the specific antibody response in rabbits that were infected systemically with A. fumigatus. Subsequently, the specific IgG- and IgA-antibody responses against these antigens were studied in patients suffering from proven IA and compared to healthy blood donors and patients with other forms of pneumonia. Furthermore, we examined how total IgG- and IgA-levels influence the diagnostic value of antibody detection in IA patients.

CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1.

Cytotoxic T cells that are present in tumors and capable of recognizing tumor epitopes are nevertheless generally impotent in eliciting tumor rejection. Thus, identifying the immune escape mechanisms responsible for inducing tumor-specific CD8(+) T-cell dysfunction may reveal effective strategies for immune therapy. The inhibitory receptors PD-1 and Tim-3 are known to negatively regulate CD8(+) T-cell responses directed against the well-characterized tumor antigen NY-ESO-1. Here, we report that the upregulation of the inhibitory molecule BTLA also plays a critical role in restricting NY-ESO-1-specific CD8(+) T-cell expansion and function in melanoma. BTLA-expressing PD-1(+)Tim-3(-) CD8(+) T cells represented the largest subset of NY-ESO-1-specific CD8(+) T cells in patients with melanoma. These cells were partially dysfunctional, producing less IFN-γ than BTLA(-) T cells but more IFN-γ, TNF, and interleukin-2 than the highly dysfunctional subset expressing all three receptors. Expression of BTLA did not increase with higher T-cell dysfunction or upon cognate antigen stimulation, as it does with PD-1, suggesting that BTLA upregulation occurs independently of functional exhaustion driven by high antigen load. Added with PD-1 and Tim-3 blockades, BTLA blockade enhanced the expansion, proliferation, and cytokine production of NY-ESO-1-specific CD8(+) T cells. Collectively, our findings indicate that targeting BTLA along with the PD-1 and Tim-3 pathways is critical to reverse an important mechanism of immune escape in patients with advanced melanoma.

Auditory localisation and recognition after left inferior collicular lesion: effects of work load on cortical activation patterns (fMRI study)

Evidence from neuropsychological and activation studies (Clarke et al., 2oo0, Maeder et al., 2000) suggests that sound recognitionand localisation are processed by two anatomically and functionally distinct cortical networks. We report here on a case of a patientthat had an interruption of auditory information and we show: i) the effects of this interruption on cortical auditory processing; ii)the effect of the workload on activation pattern.A 36 year old man suffered from a small left mesencephalic haemotrhage, due to cavernous angioma; the let% inferior colliculuswas resected in the surgical approach of the vascular malformation. In the acute stage, the patient complained of auditoryhallucinations and of auditory loss in right ear, while tonal audiometry was normal. At 12 months, auditory recognition, auditorylocalisation (assessed by lTD and IID cues) and auditory motion perception were normal (Clarke et al., 2000), while verbal dichoticlistening was deficient on the right side.Sound recognition and sound localisation activation patterns were investigated with fMRI, using a passive and an activeparadigm. In normal subjects, distinct cortical networks were involved in sound recognition and localisation, both in passive andactive paradigm (Maeder et al., 2OOOa, 2000b).Passive listening of environmental and spatial stimuli as compared to rest strongly activated right auditory cortex, but failed toactivate left primary auditory cortex. The specialised networks for sound recognition and localisation could not be visual&d onthe right and only minimally on the left convexity. A very different activation pattern was obtained in the active condition wherea motor response was required. Workload not only increased the activation of the right auditory cortex, but also allowed theactivation of the left primary auditory cortex. The specialised networks for sound recognition and localisation were almostcompletely present in both hemispheres.These results show that increasing the workload can i) help to recruit cortical region in the auditory deafferented hemisphere;and ii) lead to processing auditory information within specific cortical networks.References:Clarke et al. (2000). Neuropsychologia 38: 797-807.Mae.der et al. (2OOOa), Neuroimage 11: S52.Maeder et al. (2OOOb), Neuroimage 11: S33