Regulatory T cells represent a specialized subpopulation of T lymphocytes that may modulate spontaneous HIV-1 disease progression by suppressing immune activation or inhibiting antiviral T cell immune responses. Treg to reduce bystander immune activation while only minimally inhibiting the functional properties of HIV-1-specific T cells. Frequencies of LAP+ CD4 Treg were not significantly reduced in HIV-1 infection and unrelated to immune activation. These data indicate Moxalactam Sodium an important role of HLA-G+ Treg for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression. Author Summary HIV-1 causes disease by inducing a chronic inflammatory state that leads to progressive CD4 T cell losses and clinical signs of immune deficiency. Regulatory T cells (Treg) represent a subgroup of T lymphocytes with immunosuppressive activities that can reduce HIV-1 associated immune activation but may also worsen HIV-1 disease progression by inhibiting T cell responses directed against HIV-1 itself. Here we describe a nonclassical population of regulatory T cells that differ from conventional Treg by the expression of HLA-G a molecule that contributes to maternal tolerance against semiallogeneic fetal tissue during pregnancy. We show that HLA-G-expressing Treg have a unique functional ability to Moxalactam Sodium reduce harmful bystander immune activation while minimally inhibiting potentially beneficial T cell-mediated immune responses against HIV-1. In this way HLA-G-expressing Treg may represent a previously unrecognized barrier against HIV-1 associated immune activation and a possible target for future immunotherapeutic interventions in HIV-1 infection. Introduction The hallmark of HIV-1 infection is a progressive reduction of CD4 T cells. The main function of these cells is to provide antigen-specific helper cell activity against a wide panel of microbial antigens however some of these cells also have regulatory immunosuppressive activities. Classical regulatory T cells (Treg) are immunophenotypically defined as being CD25hi and CD127lo and they intracellularly express the Forkhead Box P3 protein (FoxP3) [1]. The importance of classical Treg for maintaining immune homeostasis has been highlighted by signs of autoimmune pathology that occur in the setting of deficient Treg activity [2] [3]. During progressive HIV-1 infection the relative frequency of classical Treg is increased while their absolute counts are reduced as a consequence of lower total CD4 T cell counts [4]. This indicates that classical Treg decline at a slower rate than conventional CD4 T cells during progressive HIV-1 infection and suggests that these cells may Moxalactam Sodium play an important role in the immune pathogenesis of Moxalactam Sodium HIV-1 infection. Functional data from previous studies indeed demonstrated Rabbit Polyclonal to CEP76. that classical Treg can potently suppress HIV-1-specific T cell responses [5] [6] and in this way may contribute to the failure of achieving T cell-mediated immune control of HIV-1 replication. However classical Treg may also have beneficial effects on HIV-1 disease progression by reducing the deleterious consequences of HIV-1 associated immune activation [7] [8]. Recently several alternative Treg populations have been identified that differ from classical Treg by the lack of intracellular FoxP3 expression. One group of such non-classical Tregs is defined by surface Moxalactam Sodium expression of HLA-G [9] an HLA class Ib molecule that is mainly expressed on placental trophoblasts. However ectopic expression of HLA-G can also be observed on small populations of peripheral blood CD4 and CD8 T cells which seem to be enriched at sites of inflammation [9]. These cells have the ability to suppress proliferation of T lymphocytes in a cell-contact independent manner and their regulatory effects are reversible following neutralization with HLA-G blocking antibodies [10]. Previous reports suggested that the proportion of HLA-G-expressing CD8 T lymphocytes is increased during HIV-1 infection [11] however such investigations were conducted in unselected populations of HIV-1 positive persons and did not address the functional role of HLA-G+ T cells during different stages of HIV-1 disease progression. A second group of nonclassical Tregs is characterized by surface expression of the latency-associated peptide (LAP) a membrane bound form of TGF-β [12]. These LAP+ CD4 T cells lack FoxP3 expression but can inhibit proliferative activities of T lymphocytes and infection assays CD4 T cells were activated Moxalactam Sodium with recombinant IL-2 (50 U/ml) and an.