Two different modes of costimulation predispose human T lymphocytes to differential responses in the presence of HDL or oxidized LDL.

In addition to levels of high-density lipoprotein (HDL), oxidized (ox) low-density lipoprotein (LDL), the inflammatory process and certain genetic factors, T cells are crucial for expansion of atherosclerotic plaque. The interrelationships among these influences are still being defined. Here, we examined how HDL and oxLDL affect T cell function. T cells require two activation signals to achieve functional activity. The first signal is specific and is delivered by appropriately presented antigen. The second (costimulatory) signal can be received through any of several T cell surface proteins, the most widely studied of which are CD28 and LFA-1. We have identified ICAM-1, resident on T cells, as a costimulatory protein. Here, we describe differential effects when T cells were costimulated through either LFA-1 or ICAM-1 in the presence of HDL or oxLDL. In general, T cells costimulated through either LFA-1 or ICAM-1 in the presence of oxLDL were predisposed to a decrease in proliferation and increased apoptosis, although ICAM-1-costimulated cells were protected from apoptosis induced by lower levels of oxLDL. T cell subsets also were examined. In the presence of HDL, CD8(+) T cells increased proliferation when costimulated through LFA-1. HDL exerted no effect on proliferation of CD4(+) T cells whereas proliferation decreased in the presence of oxLDL. Naïve T cells proliferated better in response to costimulation through LFA-1 in the presence of HDL but proliferation of effector/memory cells was not altered in the presence of HDL. When T cells were costimulated through LFA-1, in the presence of either HDL or oxLDL synthesis of Th-1 but not Th-2 cytokines was increased. T cells costimulated through ICAM-1 increased Th-1 but not Th-2 cytokines but this was not altered in the presence of HDL or oxLDL. Thus, the nature of costimulation seems to influence T cell responses in the presence of the lipoproteins.

MIP-1alpha induces differential MAP kinase activation and IkappaB gene expression in human B lymphocytes.

The chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) stimulates migration of B cells and affects B cell immunoglobulin production. However, the molecular mechanisms by which MIP-1alpha modulates these biologic effects have not been completely defined. Previously, we demonstrated that treatment of B cells with MIP-1alpha induced the transcription factor, nuclear factor (NF)-kappaB, to bind to DNA, concomitant with the degradation of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB activation. Here, we report that MIP-1alpha treatment of tonsil B cells induced IkappaB gene expression that was dependent on MIP-1alpha-mediated activation of a pathway(s) involving NF-kappaB and phosphatidylinositol-3 kinase (PI3K). The NF-kappaB pathway is understood to be controlled in an autoregulatory fashion, so expression of IkappaB is thought to provide a means by which B cells modulate this pathway after stimulation with MIP-1alpha. Although the idea of NF-kappaB autoregulation is not novel, this is the first report to suggest the regulation of B cell gene expression by MIP-1alpha. In addition, we observed the activation of Jun N-terminal kinase (JNK) and p38 mitogenic-activated protein kinase (MAPK), but not extracellular signal-related kinase (ERK) in response to MIP-1alpha. Although p38 and NF-kappaB activity were both necessary for B cell migration, IkappaB gene expression was not affected by p38 inhibition, suggesting that p38 is involved in a separate MIP-1alpha-mediated signal transduction pathway.