Role of IL-7 in immune activation during HIV-1 infection

Viral replication, lymphopenia and microbial translocation at the mucosal surfaces lead to a chronic state of immune activation during HIV-1 infection. Chronic immune activation is believed to impact on the functionality of cell types that are not the main target for virus replication, including CD8+T cells, B cells and NK cells. In this thesis two main aspects of the pathogenesis of HIV-1 infection were studied: 1) how viral replication and disease progression affect the homeostasis of peripheral NK cell subsets and functionality of CD28T cells and 2) the impact of the lymphopeniaassociated cytokine IL-7 in promoting immune activation via its priming role for T cells proliferation and its indirect effects on B cells and NK cells. Specifically, in paper I we show that an altered expression of CD70 and CD27 molecules on NK cells, as well as an altered distribution of NK cell subsets, occurs during HIV-1 infection in parallel with disease progression. Our data suggest that during the chronic phase of HIV-1 infection there is a general increased expression of CD70 on NK cells and an expansion of the immunomodulatory NK cell subset (CD56). Since CD56 NK cells can secrete large amount of proinflammatory cytokines, our data imply that NK cells can potentially contribute to immune activation, via proinflammatory cytokines and bystandard activation of CD27 expressing cells. In paper II we demonstrate that IL-7 promotes Fas induced proliferative signals on suboptimally activated T cells. Our group has previously shown that during HIV-1 infection IL-7 induces Fas expression and increases Fas mediated apoptosis of T cells. Since IL-7 is a major inducer of lymphopenia induced homeostatic T cell expansion, and is often found at high level during lymphopenia, we propose that Fas-induced proliferative signals of weakly activated T cells can contribute to T cell activation in HIV-1 infected patients. In paper III we investigated the phenotypic, survival and proliferative characteristics of CD28T cells and analyzed the impact of viral replication on their functionality. Our data suggest that viremia induces accumulation of apoptosis-prone, senescent CD28T cells. Thus we propose that control of HIV-1 replication with an early initiation of ART, might be beneficial for survival and functionality of this effector/memory subset, often specific for pathogens that establish chronic infections. In papers IV and paper V we studied the indirect effects of IL-7 on B cell homeostasis, a mechanism which may be potentially important in the settings of HIV-1 infection or in other conditions characterized by increased levels of IL-7. In paper IV, we report that IL-7 induces Fas expression on resting B cells and increases their sensitivity to apoptosis via the induction of IFN-γ production by T cells. In Paper V we show that IL-7 is able to upregulate CD70 expression on T cells, which can ultimately lead to IgG production by triggering of the CD27 molecules on B cells. Lymphopenia, through the increased IL-7 concentration, may thus confer non-antigen activated T cells with general effector function, as demonstrated by the release of IFN-γ and induction of CD70. Such mechanisms could contribute to improve immunological responses, in a situation when the immune system is weakened by lymphopenia, at the price of less regulated T cell responses contributing to bystander damage of the B cell pool. Overall paper IV and paper V illustrate novel mechanisms by which IL-7, a T cell trophic cytokine, can contribute to impaired B cell homeostasis; these findings should possibly be considered when using IL-7 therapy aiming at restoring T cells numbers in lymphopenic patients. LIST OF PUBLICATIONS I. Titanji K, Sammicheli S, De Milito A, Mantegani P, Fortis C, Berg L, Kärre K, Travi G, Tassandin C, Lopalco L, Rethi B, Tambussi G, Chiodi F. Altered distribution of natural killer cell subsets identified by CD56, CD27 and CD70 in primary and chronic human immunodeficiency virus-1 infection. Immunology. 2008 Feb;123(2):164-70. Epub 2007 Jul 11. II. Rethi B, Vivar N, Sammicheli S, Fluur C, Ruffin N, Atlas A, Rajnavolgyi E, Chiodi F. Priming of T cells to Fas-mediated proliferative signals by interleukin-7. Blood. 2008 Aug 15;112(4):1195-204. Epub 2008 Apr 25. III. Vivar N, Ruffin N, Sammicheli S, Hejdeman B, Rethi B, Chiodi F. Survival and proliferation of CD28T cells during HIV-1 infection relate to the amplitude of viral replication. J Infect Dis. 2011 Jun 1;203(11):165867. IV. Sammicheli S, Pham TH, Dang LVP, Pensieroso S, Vivar N, Ruffin N, Hejdeman B, Chiodi F , Rethi B.IL-7 promotes CD95-induced apoptosis in B cells via the IFN-γ/STAT1 pathway (Submitted) V. Sammicheli S, Ruffin N, Vivar N, Chiodi F, Rethi B.IL-7 modulates IgG production inducing CD70 expression on T cells (Manuscript)