Stress and social isolation increase vulnerability to stroke.

Stress is a universal experience for living organisms. Under many circumstances activation of the hypothalamic-pituitary adrenal (HPA) axis is an adaptive response to stress. However, when stress or HPA activation is prolonged or its timing immediately precedes or coincides with an ongoing neurodegenerative process, the results can be deleterious. A causal relationship among stress, HPA axis activity, and stroke outcome exists. Stress is one of many potential triggers of ischemic stroke and sustained elevations in glucocorticoids compromise neuronal survival following an ischemic attack. Indeed, glucocorticoid exposure is a critical determinant of stroke outcome; prior exposure to stress and elevated peri-ischemic glucocorticoid concentrations are associated with poor outcome among stroke patients and in rodent models of cerebral ischemia. Likely, stress and glucocorticoid exposure exacerbate stroke by sensitizing the neuroimmune response to ischemia; stroke induces an upregulation of pro-inflammatory cytokines which contributes to migration of leukocytes into cerebral tissue and neuronal death. Social isolation also appears to compromise stroke outcome through priming of the neuroimmune system. Among individuals who survive the stroke, residual inflammation is apt to further compromise quality of life via its effect on cognitive function and affect. A better understanding of the mechanisms through which stress and social environment modulate neuroimmune function could lead to improved treatment of stroke and other neurodegenerative diseases.

Oxytocin mediates social neuroprotection after cerebral ischemia.

BACKGROUND AND PURPOSE: The reduced incidence, morbidity, and mortality of stroke among humans with strong social support have been well-documented; however, the mechanisms underlying these socially mediated phenomena remain unknown, but may involve oxytocin (OT), a hormone that modulates some aspects of social behavior in humans and other animals. METHODS: In the present study, adult male mice were socially isolated (housed individually) or socially paired (housed with an ovariectomized female); social pairing increased hypothalamic OT gene expression. To determine whether a causal relationship exists between increased OT and improved stroke outcome, mice were treated with exogenous OT or OT receptor antagonist beginning 1 week before induction of experimental stroke via middle cerebral artery occlusion. RESULTS: Relative to social isolation, social housing attenuated infarct size, neuroinflammation, and oxidative stress following experimental stroke; the neuroprotective effect of social housing was eliminated by receptor antagonist treatment. In contrast, administration of OT to socially isolated mice reproduced the neuroprotection conferred by social housing. We further report evidence for a direct suppressive action of OT on cultured microglia, which is a key instigator in the development of neuroinflammation after cerebral ischemia. CONCLUSIONS: These findings support the hypothesis that OT mediates the neuroprotective effect of social interaction on stroke outcome.

Dendritic cells loaded with tumor B cells elicit broad immunity against murine gammaherpesvirus 68 but fail to prevent long-term latency.

It is still unknown whether a noninfectious gammaherpesvirus vaccine is able to prevent or reduce virus persistence. This led us to use dendritic cells loaded with tumor B cells as a vaccine approach for the murine gammaherpesvirus 68 (gammaHV68) model of infection. Dendritic cells loaded with UV-irradiated latently infected tumor B cells induce broad, strong, and long-lasting immunity against gammaHV68. Dendritic cell vaccination prevents the enlargement of lymph nodes and severely limits acute infection and early latency but does not prevent gammaHV68 from establishing long-term latency. Our findings support the concept that attenuated viruses may be the best vaccine option for preventing gammaherpesvirus persistence.

Persistent gamma-herpesvirus infection induces a CD4 T cell response containing functionally distinct effector populations.

The direct effector mechanisms of CD4 T cells during gamma-herpesvirus 68 (gammaHV68)-persistent infection are less well understood than those of their CD8 T cell counterparts, although there is substantial evidence that CD4 T cells are critical for the control of persistent gamma-herpesvirus infection. Our results show that in gammaHV68-persistently infected mice, CD4 T cells are not cytokine polyfunctional, but there is a division of labor in the CD4 T cell compartment in which CD4 T cells polarize toward two distinct populations with different effector functions: IFN-gamma producers and CD107(+) cytolytic effectors. These two CD4 T cell effector populations degranulate and produce IFN-gamma during steady state without need for exogenous antigenic restimulation, which is fundamentally different from that observed with gammaHV68-specific CD8 T cells. By using anti-IFN-gamma Ab depletions and IFN-gamma-deficient mice, we show that CD4 T cell-mediated cytotoxicity in vivo is not dependent on IFN-gamma activity. In addition, our data show that purified CD4 T cells isolated from gammaHV68-latently infected mice have the capacity to inhibit gammaHV68 reactivation from latency. Our results support the concept that CD4 T cells are critical effectors for the control of gamma-herpesvirus latent infection, and they mediate this effect by two independent mechanisms: IFN-gamma production and cytotoxicity.

CD4 T cells mediate killing during persistent gammaherpesvirus 68 infection.

CD4 T cells are critical for the control of gammaherpesvirus persistence, but their direct effector mechanisms of virus control in vivo are still poorly understood. In this study, we use murine gammaherpesvirus 68 (gammaHV68) in in vitro and in vivo cytotoxicity assays to show CD4-dependent killing of gammaHV68-loaded cells in mice persistently infected with gammaHV68. Our results underscore the cytotoxic capacity of CD4 T cells during gammaHV68 persistence.

CD25+ T cells induce Helicobacter pylori-specific CD25- T-cell anergy but are not required to maintain persistent hyporesponsiveness.

The gastric pathogen Helicobacter pylori infects over half the world's population. The lifelong infection induces gastric inflammation but the host fails to generate protective immunity. To study the lack of protective H. pylori immunity, CD4(+)CD25(+) T(reg) cells were investigated for their ability to down-regulate H. pylori-specific CD4(+)CD25(-) cells in a murine model. CD25(-) lymphocytes from infected mice were hyporesponsive to antigenic stimulation in vitro even in the absence of CD25(+) T(reg) cells unless treated with high-dose IL-2. Transfer of CD45RB(hi) naïve CD25(-) cells from infected mice into rag1(-/-) mice challenged with H. pylori resulted in severe gastritis and reduced bacterial loads, whereas transfer of CD45RB(lo) memory CD25(-) cells from H. pylori-infected mice resulted in only mild gastritis and persistent infection. CD25(-) cells stimulated in the absence of CD25(+) cells in rag1(-/-) mice promoted bacterial clearance, but lost this ability when subsequently transferred to WT mice harboring CD25(+) cells. These results demonstrate that CD25(+) cells induce anergy in CD25(-) cells in response to H. pylori infection but are not required to maintain hyporesponsiveness. In addition, CD25(+) cells are able to suppress previously activated CD25(-) cells when responding to H. pylori challenge in vivo.