93 research outputs found
Role of the Fas/FasL pathway in HIV or SIV disease
Human immunodeficiency virus disease involves progressive destruction of host immunity leading to opportunistic infections and increased rates for malignancies. Both depletion in immune cell numbers as well as defects in their effector functions are responsible for this immunodeficiency The broad impact of HIV reflects a similarly broad pattern of cell depletion including subsets that do not express viral receptors or support viral replication. Indirect cell killing, the destruction of uninfected cells, is due partly to activation of the Fas/FasL system for cell death. This death-signaling pathway is induced during HIV disease and contributes significantly to viral pathogenesis and disease
Repertoire Development and the Control of Cytotoxic/Effector Function in Human γδ T Cells
T cells develop into two major populations distinguished by their T cell receptor (TCR) chains. Cells with the αβ TCR generally express CD4 or CD8 lineage markers and mostly fall into helper or cytotoxic/effector subsets. Cells expressing the alternate γδ TCR in humans generally do not express lineage markers, do not require MHC for antigen presentation, and recognize nonpeptidic antigens. We are interested in the dominant Vγ2Vδ2+ T cell subset in human peripheral blood and the control of effector function in this population. We review the literature on γδ T cell generation and repertoire selection, along with recent work on CD56 expression and defining a cytotoxic/effector lineage within the phosphoantigen-reactive Vγ2Vδ2 cells. A unique mechanism for MHC-independent repertoire selection is linked to the control of effector function that is vital to the role for γδ T cells in tumor surveillance. Better understanding of these mechanisms will improve our ability to exploit this population for tumor immunotherapy
Clonal Selection and Population Dynamics of Vγ2/Vδ2 T Cells in Macaca Fascicularis
HIV infection increases the susceptibility to new M. tuberculosis (Mtb) infections, the risk of reactivating latent infections and the risk of rapid TB progression. γδ T cells, in particular the Vγ2Jγ1.2 subset, are thought to be part of the innate immune response to both HIV and Mtb. Importantly, both HIV and Mtb perturb gd T cells homeostasis, causing a profound and highly specific depletion of the Vγ2Jγ1.2 subset
Attenuated Disease in SIV-Infected Macaques Treated with a Monoclonal Antibody against FasL
Acute SIVmac infection in macaques is accompanied by high levels of plasma viremia that decline with the appearance of viral immunity and is a model for acute HIV disease in man. Despite specific immune responses, the virus establishes a chronic, persistent infection. The destruction of CD4+
and CD4- lymphocyte subsets in macaques
contributes to viral persistence and suggests the
importance of mechanisms for depleting both infected
and uninfected (bystander) cells. Bystander cell killing
can occur when FasL binds the Fas receptor on activated lymphocytes,
which include T and B cell subpopulations that are responding to the
infection. Destruction of specific immune cells could be an important
mechanism for blunting viral immunity and establishing persistent infection
with chronic disease. We inhibited the Fas pathway in vivo with a monoclonal
antibody against FasL (RNOK203). Here we show that treatment with anti-FasL
reduced cell death in circulating T and B cells, increased CTL and antibody
responses to viral proteins, and lowered the setpoint viremia. By blocking
FasL during only the first few weeks after infection, we attenuated SIVmac
disease and increased the life span for infected and treated macaques
Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor
Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Human cytomegalovirus (HCMV) can persistently infect humans, but how HCMV avoids
humoral immunity is not clear. The neonatal Fc receptor (FcRn) controls IgG transport from
the mother to the fetus and prolongs IgG half-life. Here we show that US11 inhibits the
assembly of FcRn with β2m and retains FcRn in the endoplasmic reticulum (ER), consequently
blocking FcRn trafficking to the endosome. Furthermore, US11 recruits the ubiquitin enzymes
Derlin-1, TMEM129 and UbE2J2 to engage FcRn, consequently initiating the dislocation of
FcRn from the ER to the cytosol and facilitating its degradation. Importantly, US11 inhibits IgGFcRn
binding, resulting in a reduction of IgG transcytosis across intestinal or placental epithelial
cells and IgG degradation in endothelial cells. Hence, these results identify the
mechanism by which HCMV infection exploits an ER-associated degradation pathway
through US11 to disable FcRn functions. These results have implications for vaccine development
and immune surveillance
Effects of 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2) and Rosiglitazone on Human Vδ2+ T Cells
BACKGROUND:Thiazolidinediones (TZD) class of drugs, and 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) are immune regulators predicted to modulate human autoimmune disease. Their effects on gammadelta T cells, which are involved in animal model and human and animal autoimmune diseases, are unknown. METHODOLOGY/PRINCIPAL FINDINGS:We characterized the activity of rosiglitazone (from the TZD class of drugs) and 15d-PGJ2 in human Vdelta2 T cells. We found that 15d-PGJ2 and rosiglitazone had different effects on Vdelta2 T cell functions. Both 15d-PGJ2 and rosiglitazone suppressed Vdelta2 T cell proliferation in response to IPP and IL2. However, only 15d-PGJ2 suppressed functional responses including cytokine production, degranulation and cytotoxicity against tumor cells. The mechanism for 15d-PGJ2 effects on Vdelta2 T cells acts through inhibiting Erk activation. In contrast, rosiglitazone did not affect Erk activation but the IL2 signaling pathway, which accounts for rosiglitazone suppression of IL2-dependent, Vdelta2 T cell proliferation without affecting TCR-dependent functions. Rosiglitazone and 15d-PGJ2 are designed to be peroxisome proliferator-activated receptor gamma (PPARgamma) ligands and PPARgamma was expressed in Vdelta2 T cell. Surprisingly, when PPARgamma levels were lowered by specific siRNA, 15d-PGJ2 and rosiglitazone were still active, suggesting their target of action induces cellular proteins other than PPARgamma. CONCLUSIONS/SIGNIFICANCE:The current findings expand our understanding of how the immune system is regulated by rosiglitazone and 15d-PGJ2 and will be important to evaluate these compounds as therapeutic agents in human autoimmune disease
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