|Cellular Immunology and Immunogenetics|
|HEAD||Prof. THEZE Jacques / firstname.lastname@example.org|
|MEMBERS||BUGAULT Florence, TAMARIT Blanche, Dr. CHAKRABARTI Lisa, DUMONTEIL Florence, GORGE Suzanne, JEANNIN Patricia, Dr. LANDIRES Ivan, PILLET Anne-Hélène, Dr. PEREZ-PATRIGEON Santiago, Dr ROSE Thierry, Dr VINGERT Benoît
In the majority of the patients, HIV infection progressively leads to a profound immune deficiency resulting from the dysfunction and ultimately the loss of helper CD4+ T lymphocytes. Our Unit studies the cellular and molecular mechanisms that underlie these dysfunctions, with a focus on the investigation of two major cytokines: IL-2 and IL-7. In addition, we aim at understanding how rare patients (less than 0.5%) maintain CD4+ T cell homeostasis and spontaneously control HIV replication in the absence of any treatment. Specifically, we are analyzing mechanisms that spare the Central Memory CD4+ compartment and allow efficient T cell responses in these “HIV Controller patients”, with the goal to design new vaccine strategies against HIV.
IL-2 and IL-7 receptors in lymphoid homeostasis: fundamental aspects
IL-2 regulates the expansion of recently activated T cells and the maintenance of CD25+ T regulatory cells (Treg). We described IL-2 receptor (IL-2R) assembly and demonstrated that IL-2 induces conformational changes of IL-2R that initiate the signal transduction cascade. We also studied the signal transduction mechanism of IL-7, a key cytokine that regulates both thymopoiesis and the homeostasis of peripheral lymphocytes. The IL-7R signalosome, consisting in the set of proteins associated to IL-7R, was characterized in primary T cells by mass spectrometry from 2D gels. Among the proteins recruited after IL-7 stimulation, two-third were found to be involved in cytoskeleton interactions and rafts formation (J. Biol. Chem. in press). These approaches will be used to define the signaling defects found in HIV-infected patients, who have defective IL-7 responses.
Regulatory dysfunction of the IL-7/IL-7R system in HIV viremic patients.
To better understand how HIV perturbs CD4(+) T-cell homeostasis, we performed a detailed analysis of IL-7R expression, IL-7 binding, and IL-7-dependent early and late signaling events in CD4+ T-cell subsets from viremic patients. Surprisingly, the IL-7-dependent phosphorylation of STAT5 was increased within all naive and memory CD4+ T-cell subsets in viremic patients. However, the basal level of pSTAT5 was also increased, indicating a constitutive activation of the JAK/STAT5 pathway in these patients. As the IL-7 functional responses measured by Bcl-2, CD25 and Foxp3 induction were impaired in viremic patient CD4+ T cells, our finding suggest that chronic activation induces downstream defects in the STAT5 signaling pathway. Thus, HIV infection perturbs IL-7 responses, which likely compromises the regenerative capacity of the CD4+ T-cell pool and may contribute to CD4+ T-cell depletion.
HIV Controller patients maintain a functional Central Memory CD4+ T cell compartment with high TCR avidity
HIV Controllers are a unique group defined by a spontaneous control of HIV-1 replication for ten years or more in the absence of anti-retroviral therapy (ARV) (O. Lambotte and J.-F. Delfraissy). We first showed that HIV-specific responses in Controllers were characterized by a preserved central memory CD4+ T cell compartment. To further investigate the memory CD4+T cells responsible for long-term anti-HIV responses, we characterized the growth kinetics, TCR repertoire and avidity for antigen of patient-derived CD4+ T cell lines specific for the dominant Gag293 peptide. When compared to those of ARV treated patients, lines from controllers showed faster growth kinetics and high functional avidity against the Gag293 peptide, as measured by IFN-γ responses. High avidity interactions between the TCR and the peptide-MHC complex were evidenced by studying MHC class II tetramer binding. Thus, HIV controllers harbor a pool of memory CD4+ T cells with the intrinsic ability to recognize minimal amounts of Gag antigen, which may explain how they maintain an active antiviral response in the face of very low viremia (PloS Pathogens, in press).
IL-2 and IL-7 responses in Idiopathic CD4+ T-cell lymphocytopenia
Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a rare CD4+ T-cell immunodeficiency of unknown etiology. Patients with ICL can develop severe opportunistic infections similar to those of HIV-infected individuals. Recent data indicate that ICL is associated with defective surface expression of the chemokine receptor CXCR4 in T cells (in collaboration with O. Lortholary et al.). We are investigating the IL-2 and IL-7 responses of ICL patients, which may account for the CXCR4 defect, and may help devise new immunotherapeutic strategies for these patients.
Keywords: HIV Pathogenesis, HIV Controllers, CD4 Lymphocytes, Interleukin-2, Interleukin-7, immunotherapy
S. Potter, C. Lacabaratz, O. Lambotte, S. Perez-Patrigeon, B. Vingert, M. Sinet, J-H. Colle, A. Urrutia, D. Scott-Algara, F. Boufassa, J-F. Delfraissy, J. Thèze, A. Venet and L.A. Chakrabarti (2007). Preserved central memory and activated effector memory CD4 + T cell subsets in HIV controllers. J. Virol. 81(24), 13904-13915 (PMID: 17928341)
A.-H. Pillet, F.Bugault, J.Thèze, L.A. Chakrabarti, and T. Rose (2009). A Programmed Switch from IL-15- to IL-2-Dependent Activation in Human NK Cells. J. Immunol.182 (10): 6267-6277 (PMID: 19414780)
S. Perez-Patrigeon, B.Vingert, O. Lambotte, J.-P. Viard, J.-F. Delfraissy, J. Thèze and L.A. Chakrabarti (2009). HIV infection impairs CCR7-dependent T cell chemotaxis independent of CCR7 expression. AIDS23 (10): 1197-1207 (PMID: 19455014)
O. Juffroy, F. Bugault, O. Lambotte, J.-P. Viard, Loïc Niel, A.Danckaert, J.F.Delfraissy, J. Thèze and L. Chakrabarti (2009). Dual mechanism for the impairment of the IL-7 responses in HIV infection: decreased IL-7 binding and abnormal activation of the JAK/STAT5 pathway. J. Virol.84 (1): 96-108 (19864382)
D. Scott-Algara, K. Balabanian, L.A.Chakrabarti, L. Mouthon L, F. Dromer , C. Didier, F. Arenzana-Seisdedos, O. Lortholary (2009). Idiopathic CD4+ T-cell lymphocytopenia is associated with impaired membrane expression of the chemokine receptor CXCR4. Blood. Dec 28. (PMID: 20038787)
Activity Reports 2009 - Institut Pasteur
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