Presynaptic regulation of astroglial excitatory neurotransmitter transporter GLT1.

The neuron-astrocyte synaptic complex is a fundamental operational unit of the nervous system. Astroglia regulate synaptic glutamate, via neurotransmitter transport by GLT1/EAAT2. Astroglial mechanisms underlying this essential neuron-glial communication are not known. We now show that presynaptic terminals regulate astroglial synaptic functions, GLT1/EAAT2, via kappa B-motif binding phosphoprotein (KBBP), the mouse homolog of human heterogeneous nuclear ribonucleoprotein K (hnRNP K), which binds the GLT1/EAAT2 promoter. Neuron-stimulated KBBP is required for GLT1/EAAT2 transcriptional activation and is responsible for astroglial alterations in neural injury. Denervation of neuron-astrocyte signaling by corticospinal tract transection, ricin-induced motor neuron death, or neurodegeneration in amyotrophic lateral sclerosis all result in reduced astroglial KBBP expression and transcriptional dysfunction of astroglial transporter expression. Presynaptic elements dynamically coordinate normal astroglial function and also provide a fundamental signaling mechanism by which altered neuronal function and injury leads to dysregulated astroglia in CNS disease.

Nonspecific recruitment of memory CD8+ T cells to the lung airways during respiratory virus infections.

Previous studies have shown that heterologous viral infections have a significant impact on pre-existing memory T cell populations in secondary lymphoid organs through a combination of cross-reactive and bystander effects. However, the impact of heterologous viral infections on effector/memory T cells in peripheral sites is not well understood. In this study, we have analyzed the impact of a heterologous influenza virus infection on Sendai virus-specific CD8(+) effector/memory cells present in the lung airways. The data show a transient increase in the numbers of Sendai virus nucleoprotein 324-332/K(b)-specific CD8(+) memory T cells in the airways of the influenza-infected mice peaking around day 4 postinfection. Intratracheal transfer studies and 5-bromo-2'-deoxyuridine incorporation demonstrate that this increase is due to the recruitment of resting memory cells into the airways. In addition, the data show that these immigrating memory cells are phenotypically distinct from the resident memory T cells of the lung airways. A similar influx of nonproliferating Sendai virus nucleoprotein 324-332/K(b)-specific CD8(+) memory T cells is also induced by a secondary (homologous) infection with Sendai virus. Together, these data suggest that inflammation can accelerate memory T cell migration to nonlymphoid tissues and is a part of the normal recall response during respiratory infections.

Long-term maintenance of virus-specific effector memory CD8+ T cells in the lung airways depends on proliferation.

Recent studies have shown that virus-specific effector memory T cells can be recovered from the lung airways long after clearance of a respiratory virus infection. These cells are thought to play an important role in the recall response to secondary viral infection. It is currently unclear whether these cells actually persist at this site or are maintained by continual proliferation and recruitment. In this study, we have analyzed the mechanisms underlying the persistence of memory CD8(+) T cells in the lung airway lumina following recovery from a respiratory virus infection. The data identify two distinct populations of memory cells. First, a large population Ag-specific CD8(+) T cells is deposited in the airways during the acute response to the virus. These cells persist in a functional state for several weeks with minimal further division. Second, a smaller population of Ag-specific CD8(+) T cells is maintained in the lung airways by homeostatic proliferation and migration to lung airways after viral clearance. This rate of proliferation is identical to that observed in the spleen, suggesting that these cells may be recent immigrants from the lymphoid organs. These data have significant implications for vaccines designed to promote cellular immunity at mucosal sites such as the lung.

Antiviral memory T-cell responses in the lung.

Recent studies have identified distinct populations of memory T cells that persist in the lungs following respiratory virus infections, and contribute to the control of secondary virus infections. Here we discuss the establishment, maintenance and recall of memory T cells in the lung.