[show abstract][hide abstract] ABSTRACT: The IL-7R alpha-chain and the common gamma-chain (gamma(c)) are both components of IL-7R. Human plasma harbors soluble forms of IL-7R (sIL-7Ralpha and sgamma(c)) that are detected and assayed by Western blotting, showing that the levels of sIL-7Ralpha are higher than the levels of sgamma(c) (47.5 ng/ml and 1.5 ng/ml, respectively). Gel electrophoresis and tandem mass spectrometry used to analyze deglycosylated, affinity-purified protein showed that sIL-7Ralpha is generated through differentially spliced mRNA, not by membrane receptor shedding. Plasma sIL-7Ralpha and sgamma(c) are present as heterocomplexes and sgamma(c) was found to be mainly associated with sIL-7Ralpha. The affinities of two IL-7 binding sites (K(d) = 35 +/- 8 pM and K(d) = 3 +/- 1 nM) were similar to that of the membrane receptor, suggesting that the sIL-7Ralpha/sgamma(c) complex retains high affinity for IL-7. sIL-7Ralpha mRNA is constitutively present among peripheral T lymphocytes and is down-modulated in vitro by IL-7. Chronically HIV-1-infected patients (n = 20) showed no significant (p > 0.714) variation in sgamma(c) levels and a significant (p < 0.0014) 2-fold decrease in plasma sIL-7Ralpha levels compared with those in control healthy individuals. Plasma IL-7 and sIL-7Ralpha levels did not show any obvious relationship.
The Journal of Immunology 06/2009; 182(12):7389-97. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: Two types of functional interleukin-2 receptor (IL-2Ralpha/IL-2Rbeta/gammac and IL-2Rbeta/gammac) have already been characterized in humans. Here we describe a new form consisting of IL-2Rbeta/beta homodimers that assemble spontaneously in the absence of gammac. Co-transfection of COS-7 cells with constructs expressing IL-2Rbeta chains tagged with either HA or MYC sequences results in the formation of IL-2Rbeta:HA/IL-2Rbeta:MYC complexes detectable by coimmunoprecipitation. The formation of these IL-2Rbeta:HA/IL-2Rbeta:MYC dimers is also observed in the absence of IL-2. Moreover, in COS cells expressing chimeras of IL-2Rbeta fused to fluorescence reporters such as IL-2Rbeta:ECFP and IL-2Rbeta:EYFP, we also observed specific FRET at the surface of living cells, as expected for dimer formation. Transiently transfected COS-7 cells expressing IL-2Rbeta bind 125I-labeled IL-2 (homodimers, Kd = 1nM) as cells expressing both IL-2Rbeta and gammac chains (heterodimers, Kd = 1 nM). IL-2Rbeta/IL-2Rbeta could represent either a decoy receptor or a new form of IL-2R involved in signaling when gammac expression is low.
[show abstract][hide abstract] ABSTRACT: Human immunodeficiency virus (HIV) controllers are rare individuals who spontaneously control HIV type 1 replication for 10 years or more in the absence of antiretroviral treatment. In the present study, HIV controllers (n = 11) maintained potent HIV-specific CD4 responses in spite of very low antigenic loads. Their CD4+ central memory T (T(CM)) cells were characterized by near-normal numbers and preserved interleukin-2 (IL-2) secretion in response to HIV antigens and uniformly high expression of the survival receptor IL-7 receptor alpha (IL-7Ralpha). Controllers expressed CCR7 at higher levels than uninfected controls, suggesting differences in T(CM)-cell homing patterns. CD4+ effector memory T (T(EM))-cell responses were polyfunctional in HIV controllers, while IL-2 secretion was lost in viremic patients. Cytokine production was three times higher in controllers than in treated patients with undetectable viral loads, suggesting an intrinsically more efficient response in the former group. The total CD4+ T(EM)-cell pool underwent immune activation in controllers, as indicated by increased HLA-DR expression, decreased IL-7Ralpha expression, a bias towards gamma interferon production upon polyclonal stimulation, and increased macrophage inflammatory protein 1beta secretion associated with chronic CCR5 down-regulation. Thus, HIV controllers showed a preserved CD4+ T(CM)-cell compartment and signs of potent functional activation in the CD4+ T(EM)-cell compartment. While controllers did not show the generalized immune activation pattern associated with disease progression, they had signs of immune activation restricted to the effector compartment. These findings suggest the induction of an efficient, nondetrimental type of immune activation in patients who spontaneously control HIV.
Journal of Virology 01/2008; 81(24):13904-15. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Measurements of Bcl-2 and CD25 expression suggested that IL-7R function is modified in CD4 lymphocytes of untreated viraemic patients. The extent of IL-7R function restoration post-HAART was analysed. A positive linear relationship was demonstrated between IL-7Ralpha expression and the magnitude of IL-7-induced responses in healthy individuals, whereas this relationship is lost in HIV-infected patients, suggesting that viraemic patients suffer a receptor signaling transduction defect in IL-7R function. IL-7 responsiveness is only partly restored by HAART.
[show abstract][hide abstract] ABSTRACT: Despite an increase in plasma IL-7 levels, the CD4 T-cell pool decrease progressively in HIV-infected patients. Here we report on our tests to check the hypothesis that defects in the IL-7 receptor system might be involved in this phenomenon. The cell surface expression of CD127 was measured ex vivo in CD4 and CD8 T lymphocytes drawn from 3 groups of HIV patients. IL-7 function was also followed in vitro by measuring IL-7-driven T-cell proliferation, the induction of the CD25 activation marker, and overexpression of the antiapoptotic molecule Bcl-2. Untreated viremic patients showed a slight but significant decrease in CD127 expression on the surface of their CD4 lymphocytes. By contrast, CD127 expression was substantially altered on the surface of CD8 T lymphocytes taken from untreated viremic patients. IL-7-induced overexpression of the antiapoptotic molecule Bcl-2 was dramatically altered in viremic patients, whereas IL-7-dependent CD25 induction and T-cell proliferation were reduced. Highly active antiretroviral therapy partially corrected these defects in patients with an undetectable viral load and CD4 counts of more than 400 cells/microL. The effects of HAART were less pronounced in patients with undetectable VL but low CD4 counts (<250 cells/microL). The IL-7 receptor is dysfunctional in the CD4 and CD8 lymphocytes of HIV-infected patients. This may be due to abnormal activation of the immune system in HIV-infected patients and may contribute to the reduced CD4 count and the altered function of the CD8 compartment.
[show abstract][hide abstract] ABSTRACT: IL-7 is a crucial cytokine regulating lymphopoiesis and peripheral T lymphocyte homeostasis. Plasma IL-7 levels increase during HIV infection and, although antiretroviral therapy (ARV therapy) decreases these levels, they fail to return to normal. Immune reconstitution in most ARV-treated patients is only partial. We tested the possibility that the IL-7R system might be affected by ARV drugs. The effects of the antireverse transcriptase AZT and the anti-protease saquinavir on CD3- and CD3+CD28-induced T lymphocyte stimulation, in the presence (or absence) of IL-7, were studied in vitro. Small amounts of the drugs did not interfere with the capacity of IL-7 to stimulate T cell proliferation, but higher concentrations significantly decreased IL-7-induced T cell proliferation both in cells from HIV-infected patients and in cells from healthy donors. IL-7 is known to down-modulate its own receptor on the surface of CD4 and CD8 T lymphocytes in vitro. In CD4 lymphocytes from healthy donors or HIV-infected patients, neither AZT, nor saquinavir, nor a combination of the two, interfered with this property. In contrast, AZT + saquinavir worsened the IL-7-induced down-regulation of CD127 expression by CD8 T cells from HIV-infected patients, while no such effect was observed with CD8 T cells from healthy donors. Our data suggest that, under certain conditions, antiretroviral therapy could interfere with the expression and function of the IL-7/IL-7R system, and more particularly it may affect the CD8-lymphocyte compartment of HIV-infected patients.
European cytokine network 01/2006; 16(4):293-9. · 1.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: IL-2 is used in conjunction with highly active antiretroviral therapy to increase the CD4 cell count in HIV-positive patients. The mechanisms involved remain ill-defined. Here we show that during the first cycle of IL-2 therapy, IL-7 and Flt-3L plasma levels are increased, whereas levels of stem cell factor are unchanged. This supports the hypothesis that aside from stimulating CD4 T cells IL-2 may also indirectly affect lymphocyte production through the stimulation of lymphopoietic cytokines.
AIDS 11/2004; 18(15):2089-91. · 6.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Highly active antiretroviral therapy (HAART) in HIV patients generally increases the CD4 cell count, but the level of CD4 cell restoration remains very heterogeneous. IL-7 is the main cytokine controlling the size of the T-cell pool. We assessed the hypothesis that pre-HAART IL-7 plasma levels may affect CD4 cell restoration after treatment. A positive correlation was found in a cohort of 18 patients between pre-HAART IL-7 plasma levels and CD4 cell increases after 20 +/- 7.8 months of HAART.