HIV Infection Deregulates the Balance Between Regulatory T Cells and IL-2-Producing CD4 T Cells by Decreasing the Expression of the IL-2 Receptor in Treg
ABSTRACT Indexation of Treg to the number of activated T-cells constitutes a homeostatic mechanism ensuring that T-cell expansion remains under control. However, immune hyperactivation observed in HIV-infected patients suggests a possible dysfunction of this mechanism. Here we show that the Treg/IL2-producing cells balance is deeply disturbed in viremic HIV-infected patients. We found a lower expression of IL2-Rα on Treg from viremic patients. We confirmed in vitro that HIV-infection of Treg downregulates IL2-Rα and pSTAT5. Our results argue for an impaired capacity of Treg to sensing the expansion of activated T-cells in HIV-infected patients that could contribute to the immune deregulation.
SourceAvailable from: Aixin Yu[Show abstract] [Hide abstract]
ABSTRACT: The importance of IL-2Rbeta function for immune regulation is highlighted by the severe impairment in lymphoid cell function in IL-2Rbeta-deficient mice. It has been speculated that failed IL-2/IL-2R signaling in peripheral T cells causes the associated autoimmunity, imbalanced peripheral lymphoid homeostasis, and defective T cell function. This study explored the requirement for IL-2Rbeta function in mature T lymphocytes. We show that transgenic thymic expression of the IL-2R beta-chain in IL-2Rbeta-deficient mice prevents lethal autoimmunity, restores normal production of B lymphocytes, and results in a peripheral T cell compartment that is responsive to triggering through the TCR, but not the IL-2R. The dysfunction of the IL-2R is illustrated by the near complete failure of mature T cells to proliferate to IL-2 in vitro and in vivo, to differentiate into CTL, and to up-regulate IL-2Ralpha expression. These data indicate that lymphoid homeostasis is largely maintained despite a nonfunctional IL-2R in mature T lymphocytes and suggest that IL-2Rbeta provides an essential signal during thymic development to regulate self-reactivity.The Journal of Immunology 04/2000; 164(6):2905-14. DOI:10.4049/jimmunol.164.6.2905 · 5.36 Impact Factor
Article: T cell dynamics in HIV-1 infection.[Show abstract] [Hide abstract]
ABSTRACT: In the absence of antiretroviral treatment, HIV-1 establishes a chronic, progressive infection of the human immune system that invariably, over the course of years, leads to its destruction and fatal immunodeficiency. Paradoxically, while viral replication is extensive throughout the course of infection, deterioration of conventional measures of immunity is slow, including the characteristic loss of CD4(+) T cells that is thought to play a key role in the development of immunodeficiency. This conundrum suggests that CD4(+) T cell-directed viral cytopathicity alone cannot explain the course of disease. Indeed, recent advances now indicate that HIV-1 pathogenesis is likely to result from a complex interplay between the virus and the immune system, particularly the mechanisms responsible for T cell homeostasis and regeneration. We review these data and present a model of HIV-1 pathogenesis in which the protracted loss of CD4(+) T cells results from early viral destruction of selected memory T cell populations, followed by a combination of profound increases in overall memory T cell turnover, damage to the thymus and other lymphoid tissues, and physiological limitations in peripheral CD4(+) T cell renewal.Annual Review of Immunology 02/2003; 21:265-304. DOI:10.1146/annurev.immunol.21.120601.141053 · 41.39 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Human immunodeficiency virus (HIV) infection leads to a profound T cell dysfunction well before the clinical onset of acquired immunodeficiency syndrome (AIDS). We have been accumulating evidence that one of the mechanisms responsible for this T cell deficiency may be the dysregulation of signal transduction via the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have observed previously that viral envelope (env) glycoproteins induce IL-2 unresponsiveness and the down-regulation of the three chains making up the IL-2R (alpha, beta, gamma) in vitro. We have now established further that this disruption of the IL-2/IL-2R system manifests itself in defective signal propagation via the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV.Clinical & Experimental Immunology 04/2003; 131(3):422-7. DOI:10.1046/j.1365-2249.2003.02065.x · 3.28 Impact Factor