Apoptosis induced in HIV-1-exposed, resting CD4+ T cells subsequent to signaling through homing receptors is Fas/Fas ligand-mediated.

The hallmark of HIV-1 disease is the gradual disappearance of CD4+ T cells from the blood. The mechanism of this depletion, however, is still unclear. Evidence suggests that lymphocytes die in lymph nodes, not in blood, and that uninfected bystander cells are the predominant cells dying. Our and others' previous studies showed that the lymph node homing receptor, CD62 ligand (CD62L), and Fas are up-regulated on resting CD4+ T cells after HIV-1 binding and that these cells home to lymph nodes at an enhanced rate. During the homing process, signals are induced through various homing receptors, which in turn, induced many of the cells to undergo apoptosis after they entered the lymph nodes. The purpose of this study was to determine how the homing process induces apoptosis in HIV-1-exposed, resting CD4+ T cells. We found that signaling through CD62L up-regulated FasL. This resulted in apoptosis of only HIV-1-presignaled, resting CD4+ T cells, not normal CD4+ T cells. This homing receptor-induced apoptosis could be blocked by anti-FasL antibodies or soluble Fas, demonstrating that the Fas-FasL interaction caused the apoptotic event.

Suppressed clinical experimental autoimmune myasthenia gravis in bm12 mice is linked to reduced intracellular calcium mobilization and IL-10 and IFN-gamma release by acetylcholine receptor-specific T cells.

Class II MHC mutant bm12 mice have an increased resistance to experimental autoimmune myasthenia gravis (EAMG) compared to C57BL/6 mice. In vitro, this relative resistance was mainly associated with a reduced cytokine response to acetylcholine receptor (AChR) and its dominant pathogenic peptide alpha 146-162, whereas the response to the epitope alpha 111-126 remained intact. Calcium mobilization after stimulation of AChR-immune T cells with AChR or alpha 146-162 peptide, but not alpha 111-126 peptide, was decreased in bm12 compared to C57BL/6. Thus, the reduced incidence of clinical EAMG in bm12 is linked to lower IFN-gamma and IL-10 release, and intracellular calcium mobilization by alpha 146-162-specific T cells.

HIV-1 induces IL-10 production in human monocytes via a CD4-independent pathway.

In HIV-infected patients, increased levels of IL-10, mainly produced by virally infected monocytes, were reported to be associated with impaired cell-mediated immune responses. In this study, we investigated how HIV-1 induces IL-10 production in human monocytes. We found that CD14(+) monocytes infected by either HIV-1(213) (X4) or HIV-1(BaL) (R5) produced IL-10, IL-6, tumor necrosis factor-alpha (TNF-alpha), and to a lesser extent, IFN-gamma. However, the capacity of HIV-1 to induce these cytokines was not dependent on virus replication since UV-inactivated HIV-1 induced similar levels of these cytokines. In addition, soluble HIV-1 gp160 could induce CD14(+) monocytes to produce IL-10 but at lower levels. Cross-linking CD4 molecules (XLCD4) with anti-CD4 mAbs and goat anti-mouse IgG (GAM) resulted in high levels of IL-6, TNF-alpha and IFN-gamma but no IL-10 production by CD14(+) monocytes. Interestingly, neither anti-CD4 mAbs nor recombinant soluble CD4 (sCD4) receptor could block IL-10 secretion induced by HIV-1(213), HIV-1(BaL) or HIV-1 gp160 in CD14(+) monocytes, whereas anti-CD4 mAb or sCD4 almost completely blocked the secretion of the other cytokines. Furthermore, HIV-1(213) could induce IL-10 mRNA expression in CD14(+) monocytes while XLCD4 by anti-CD4 mAb and GAM failed to do so. As with IL-10 protein levels, HIV-1(213)-induced IL-10 mRNA expression in CD14(+) monocytes could not be inhibited by anti-CD4 mAb or sCD4. Taken together, HIV-1 binding to CD14(+) monocytes can induce CD4-independent IL-10 production at both mRNA and protein levels. This finding suggests that HIV induces the immunosuppressive IL-10 production in monocytes and is not dependent on CD4 molecules and that interference with HIV entry through CD4 molecules may have no impact on counteracting the effects of IL-10 during HIV infection.

All roads lead to actin: the intimate relationship between TCR signaling and the cytoskeleton.

Regardless of cell type, the regulation of the actin cytoskeleton is tightly linked to vital biological properties such as polarity, motility, cell-cell contact, exocytosis and proliferation. In the immune system, where rapid and efficient response to antigen-provoked stimuli is crucial, an overwhelming amount of data implicate the actin cytoskeleton and its regulators as central to immune function. Increasingly, the cytoskeleton is considered an essential amplification step in T cell receptor (TCR)-, costimulatory-, and integrin-mediated signaling. Advances in genetic manipulation and confocal imaging have led to a keener appreciation of the importance of TCR signal integration by the actin cytoskeleton. This review outlines recent advances in elucidating the regulation of T cell function through the actin cytoskeleton. We also examine intriguing parallels between the immune system and other models of cytoskeletal regulation.