Chemokine CXCL10 (IP-10) is sufficient to trigger an immune response to injected antigens in a mouse model.

The induction of chemokines by interferons might represent a link between innate and adaptive immunity. Whether these induced chemokines might be useful by themselves to induce an immune response is not known. We hypothesized that the interferon-inducible chemokine CXCL10 could stimulate dendritic cells (DC) to mature and cross-present exogenous antigen to T cells, resulting in a Th1-type immune response. We found that injecting mice with CXCL10 together with ovalbumin (OVA) as a test antigen was sufficient to produce functional OVA-specific T cells in 7 of 10 mice. Further, using only CXCL10 and a peptide antigen derived from vaccinia virus, we were able to induce peptide-specific cytotoxic T cells in 4 of 4 mice tested. These cytotoxic T cells protected 9 of 10 mice from subsequent infectious challenge with vaccinia virus. Unlike traditional adjuvants, no side effects were observed in any of the injected mice. We conclude that CXCL10 co-administration with a variety of antigens may represent a unique strategy of inducing a protective T cell response to a number of pathogens that merits further study.

Abnormal presence of semimature dendritic cells that induce regulatory T cells in HIV-infected subjects.

Dendritic cells (DCs), because they orchestrate the immune response to microbes, represent an ideal target for pathogens attempting to evade the immune system. We hypothesized that interactions between human immunodeficiency virus (HIV) and DCs lead to the development of a semimature state, in which DCs migrate to lymph nodes but induce tolerance in T cells, rather than immunity. We found that lymph nodes from untreated HIV-infected subjects contained an abundance of semimature DCs, the disappearance of which correlated with the initiation of highly active antiretroviral therapy (HAART). Such lymph nodes also contained an abundance of T cells that had a regulatory phenotype and that persisted after HAART. Lymph node DCs from untreated HIV-infected subjects cultured with normal allogeneic T cells induced these T cells to adopt the phenotype of regulatory T cells, an ability that was lost after HAART. We conclude that HIV infection correlates with the presence of semimature DCs that stimulate T cell tolerance rather than immunity. These regulatory T cells may contribute to the lack of effective HIV immune responses.

Chemokines promote quiescence and survival of human neural progenitor cells.

Many cell types in the brain express chemokines and chemokine receptors under homeostatic conditions, arguing for a role of these proteins in normal brain processes. Because chemokines have been shown to regulate hematopoietic progenitor cell proliferation, we hypothesized that chemokines would regulate neural progenitor cell (NPC) proliferation as well. Here we show that chemokines activating CXCR4 or CCR3 reversibly inhibit NPC proliferation in isolated cells, neurospheres, and in hippocampal slice cultures. Cells induced into quiescence by chemokines maintain their multipotential ability to form both neurons and astrocytes. The mechanism of chemokine action appears to be a reduction of extracellular signal-related kinase phosphorylation as well as an increase in Reelin expression. The inhibitory effects of chemokines are blocked by heparan sulfate and apolipoprotein E3 but not apolipoprotein E4, suggesting a regulatory role of these molecules on the effects of chemokines. Additionally, we found that the chemokine fractalkine promotes survival of NPCs. In addition to their role in chemotaxis, chemokines affect both the survival and proliferation of human NPCs in vitro. The presence of constitutively expressed chemokines in the brain argues that under homeostatic conditions, chemokines promote survival but maintain NPCs in a quiescent state. Our studies also suggest a link between inflammatory chemokine production and the inhibition of neurogenesis.

HIV-1 promotes quiescence in human neural progenitor cells.

The exact mechanism by which human immunodeficiency virus type 1 (HIV-1) produces dementia remains obscure. We have recently found that chemokines can inhibit neural progenitor cell proliferation. We hypothesized that HIV-1 could also inhibit neural progenitor cell proliferation by chemokine receptor signaling. We found that HIV-1 coat proteins that used C-C chemokine receptor 3 or C-X-C chemokine receptor 4 as coreceptors inhibited proliferation of neural progenitor cells in isolated cultures, as well as in hippocampal slices. The cerebrospinal fluid from patients with dementia also inhibited neural progenitor cell proliferation in these culture systems. To obtain an in vivo correlation, we examined hippocampus tissue obtained from patients with dementia at autopsy and found reduced numbers of neural progenitor cells in patients with dementia, compared with patients without dementia. Apolipoprotein E3, but not E4, antagonized the effects of coat proteins. We found reduced phosphorylation of extracellular signal-regulated kinase in neural progenitor cells treated with coat proteins, which may explain the protein's mechanism of action. We conclude that HIV-1 inhibits neural progenitor cell proliferation, which may result in impaired ability to form new memories and learn new tasks.

Rates and risks of transmission of smallpox and mechanisms of prevention.

In 1980, the World Health Organization declared smallpox eradicated from the world; the last known natural case had occurred in Somalia in 1977, and the United States had stopped routinely vaccinating its citizens in 1972. However, with increasing concerns regarding domestic and international terrorism, smallpox has resurfaced as a potential threat to global health. We review the direct and indirect modes of smallpox transmission and how patterns of transmission vary substantially, depending on the severity of circulating disease, vaccination status, environmental and socioeconomic factors, and the setting of an outbreak. We examine mechanisms for controlling outbreaks of disease and preventing further transmission in the event of an outbreak, with an emphasis on smallpox vaccination.