Maintaining T cell polyfunctionality

In order to protect the body from viruses and cancer, T cells must perform multiple functions, a feature that is often lost during chronic infection. Jonathan Schneck and colleagues examined the molecular mechanisms that maintain T cell polyfunctionality. They found that MAPK/ERK signaling was upregulated in polyfunctional T cells and that activation of this pathway was altered in response to different levels of antigen. Importantly, high levels of antigen increased levels of sprouty-2 (SPRY2), a negative regulator of MAPK/ERK signaling. High levels of SPRY2 were observed in HIV-specific T cells and inhibition of SPRY2 expression increased polyfunctional responses to HIV. These findings suggest that SPRY2 could be targeted to increase T cell polyfunctionality in the context of chronic viral infections.

Protecting the kidney through ion channel inhibition

Damage to the glomerulus, which mediates the kidney's filtering function, causes plasma protein to spill into the urine, a sign of kidney failure and cardiovascular disease. Calcium influx into the podocytes, the cells that form the filtration barrier of the glomerulus, is known to damage the glomerulus, but the ion channel that mediates this influx was unknown. In this episode, Anna Greka and colleagues discuss their recent work demonstrating that inhibition of the TRPC5 ion channel protects mice from kidney damage by preventing calcium influx into the podocytes, and blocks the cytoskeletal alterations in the podocytes that disrupts the filtration barrier in the glomerulus.

Exploring long-term expression of therapeutic transgenes

Results from early-phase clinical trials have indicated that recombinant adeno-associated viruses (rAAV) could potentially be used for gene therapy. In each trial, however, patients have developed T cell-mediated immune responses that may interfere with therapeutic gene expression. In this episode, Terence Flotte and Christian Mueller discuss their recent study investigating T cell responses to intramuscular injection of a rAAV encoding M-type a1-antitrypsin (AAT) in patients with AAT-deficiency. Their results demonstrate that AAT expression persists for up to 12 months and suggest that immunomodulation of T cell populations may not be necessary for long-term, rAAV-mediated transgene expression.

Regulating immune activation by necrotic cells

In order to mount an effective immune response, T cells must be primed with the appropriate antigens to help them recognize malignant or pathogen-infected cells. Tim Greten and colleagues examined how necrotic cell death influences T cell cross-priming. Here they report on a molecular mechanism that blocks antigen cross-presentation by necrotic cells. Moreover, they found that this mechanism could be circumvented to promote immunogenicity of tumor cells.

Researchers characterize antibodies that block H5N1 influenza viral transmission

H5N1 avian influenza is a highly pathogenic virus that has been responsible for several outbreaks of bird flu in humans over the past decade. In previous outbreaks, the virus spread through direct contact between humans and infected birds, but was not able to spread from human to human. Recent studies in ferrets have demonstrated that mutations in the viral HA gene allow the virus to be transmitted via respiratory droplets indicate that such mutations may also make the virus transmissible between humans. In this episode, James Crowe of Vanderbilt University describes his group’s recent investigation of the ability to human H5N1 vaccines to neutralize respiratory droplet transmissible forms of the virus. Using peripheral blood mononuclear cells from vaccinated humans, Crowe and colleagues identified antibodies that recognized both wild type and respiratory droplet transmissible forms of viral HA. Structural studies were used to further characterize the motifs required for antibody recognition.  These findings indicate that the polyclonal sera currently used for vaccination can neutralize respiratory droplet transmissible forms of the virus.