|Cellular Immunology and Immunogenetics|
|HEAD||Prof. THEZE Jacques / email@example.com|
|MEMBERS||BENATI Daniela, BUGAULT Florence, Dr. CHAKRABARTI Lisa, DUMONTEIL Florence, JEANNIN Patricia, Dr. LANDIRES Ivan, Dr ROSE Thierry, TAMARIT Blanche, 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 characterize correlates of HIV protective responses. Altogether our investigations aim at devising new approaches for immunotherapy and new concepts in the design of 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 modeled 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. Among the proteins recruited after IL-7 stimulation, two-third were found to be involved in cytoskeleton interactions and rafts formation. Based on these findings, we built a model describing the different steps of the compartmentalization of the IL-7R signalosome. This work informs on the role of rafts in the organization of the functional receptor and on the role of the cytoskeleton in the transport of the signaling molecules to the nucleus (J. Biol. Chem. 2010).
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. In addition, 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. Indeed, our recent findings suggest that STAT5 nuclear translocation is defective in CD4+ T lymphocytes from viremic patients, which may account for perturbed IL-7 responses. We plan to further investigate the mechanisms by which abnormal activation of the immune system alters cytokine signal transduction pathways, which may compromise the regenerative capacity of the CD4+ T cells and contribute to their depletion in HIV infection.
HIV Controller patients maintain a functional Central Memory CD4+ T cell compartment with high TCR avidity
HIV Controllers are a unique group of patients 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 immunodominant Gag peptides. When compared to those of ARV treated patients, cell lines from controllers showed faster growth kinetics and high functional avidity against the Gag293 peptide, as measured by IFN-γ responses. The high functional avidity could be explained by a strong interaction between the TCR and the peptide-MHC complex, as demonstrated by 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, 2010).
IL-2 and IL-7 responses in Idiopathic CD4 Lymphocytopenia
Idiopathic CD4 Lymphocytopenia (ICL) is a rare CD4+ T-cell immunodeficiency of unknown etiology. Patients with ICL can develop severe opportunistic infections very similar to those seen in AIDS. We have found that IL-2 and IL-7 responses were impaired in ICL, which may play a significant role in the loss of CD4+ T cells. Intriguingly, responses to the IL-7-like cytokine TSLP (Thymic Stromal Lymphopoietin) were increased rather than decreased in ICL, suggesting a compensatory mechanism susceptible to limit the loss of CD4+ T cells in siuations of defective IL-7 signaling. These findings shed light on the fundamental mechanisms regulating T cell homeostasis in humans.
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)
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)
B. Vingert, S. Perez-Patrigeon, P. Jeannin, O. Lambotte, F. Boufassa, F. Lemaitre, W. W. Kwok, I. Theodorou, J.-F. Delfraissy, J. Thèze and L. Chakrabarti (2010). HIV Controller CD4+ T Cells Respond to Minimal Amounts of GagAntigen Due to High TCR Avidity. PloS Pathogens6 (2): e1000780
T. Rose, A.-H. Pillet, V. Lavergne, B. Tamarit, P. Lenormand, J.-C. Rousselle, A. Namane and J. Thèze (2010). Interleukine-7 compartimentilizes its receptor signaling complex to initiate CD4 T lymphocyte response. J. Biol. Chem. 285 (20): 14898-14908 (20816854)
Activity Reports 2010 - Institut Pasteur
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