|Cellular Immunology and Immunogenetics|
|HEAD||Prof. THEZE Jacques / firstname.lastname@example.org|
|MEMBERS||BUGAULT Florence, BLOM-POTAR Marie-Christine, Dr CHAKRABARTI Lisa, DUMONTEIL Florence, JUFFROY Olivier, PILLET Anne-Hélène, Dr PEREZ-PATRIGEON Santiago, Dr ROSE Thierry, Dr VINGERT Benoît
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, which controls the expansion of recently activated T cells and the maintenance of CD25+ T regulatory cells (Treg), and IL-7, which regulates both thymopoiesis and the homeostasis of peripheral lymphocytes. Our findings support a major role for these two cytokines in the pathogenesis of HIV infection.
IL-2 and IL-7 receptors in lymphoid homeostasis: fundamental aspects
Natural Killer (NK) cell activity in early antiviral responses is tightly regulated by cytokines. We have shown that NK cells stimulated by IL-2, IL-7 or IL-15 develop a unique cytokine receptor expression program linking innate and adaptative immune responses. Tregs play a critical role in the control of the overall activation of the immune system. We observed that, in spite of low expression levels of the IL-7R (CD127) at the surface of naïve and memory Tregs, both sub-populations maintained a response to IL-7. We have now launched a proteomic characterization of the IL-7R signalosome, to better understand signaling pathways involved in lymphocyte homeostasis.
Abnormal activation and dysfunction of the IL-7 system in viremic patients. We obtained evidence for increased basal activation levels of the JAK/STAT pathway in CD4+ T cells of viremic patients, supporting the notion of an abnormal immune activation in HIV infection. However, functional
responses such as Bcl-2 induction are impaired, demonstrating a block in IL-7-dependent survival pathways. Thus, CD4+ T cells that express near normal levels of CD127 show both hyperactivation and defects in downstream signaling pathways. These defects may impair the IL-7 / CD4+ T cell homeostatic regulatory loop and contribute to the CD4+ T cell depletion characteristic of HIV infection.
HIV Controller patients preserve a functional Central Memory CD4+ T cell compartment
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 show that HIV-specific responses in Controllers are characterized by a preserved central memory CD4+ T cell compartment with intact IL-2 secretion capacity, and by a non-detrimental immune activation of the effector memory CD4+ T cell compartment.
Therapeutic potential of IL-2 and IL-7
In ARV-treated patients with low CD4 counts, IL-2 cycles rapidly induce the appearance of a new CD4+ CD45RA+ CD25+ T lymphocyte population with some Treg characteristics. These lymphocytes are under molecular characterization (in collaboration with L. Rogge). In viremic patients, we showed that ARV reversed IL-7R functional defects, thus opening the way to ongoing IL-7 immunotherapy trials.
Keywords: HIV Pathogenesis, HIV Controllers, CD4 Lymphocytes, Interleukin-2, Interleukin-7
M. Kryworuchko, V. Pasquier, H. Keller, D. David, C. Goujard, J. Gilquin, J-P. Viard, M. Joussemet, J-F. Delfraissy and J. Thèze (2004). Defective IL-2-dependent STAT 5 signaling in CD8 T lymphocytes from HIV-positive patients : restoration by antiretroviral therapy. AIDS 18(3), 421-426. (PMID: 15090793)
E. Assier, V. Jullien, J. Lefort, J.-L. Moreau, J. Di Santo, B.B. Vargaftig, J.-R. Lapa e Silva and J. Thèze (2004). NK and polymorphonuclear neutrophils are both critical for IL-2-induced pulmonary vascular leak syndrome. J. Immunol.172, 7661 - 7668. (PMID: 15187148)
F. Gesbert, J-L. Moreau and J. Thèze (2005). IL-2 responsiveness of CD4 and CD8 lymphocytes : Further investigations with human IL-2R beta transgenic mice. Int. Immunol. 17(8), 1093-1102. (PMID: 16037071)
J-H. Colle, J-L. Moreau, A. Fontanet, O. Lambotte, M. Joussemet, S. Jacod, J-F. Delfraissy and J. Thèze (2006). Regulatory dysfunction of the interleukin-7 receptor in CD4 and CD8 lymphocytes from HIV-infected patients - effects of antiretroviral therapy. J. Acquir. Immune. Defic. Syndr. 42(3), 277-285. (PMID: 16810123)
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: an ANRS EP36 study. J. Virol. 81 (24), 13904-13915 (PMID: 17928341)
Activity Reports 2007 - Institut Pasteur
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