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December 2008--They patrol our bodies like state troopers navigating the Maryland highways. More specifically, they’re akin to officers in unmarked cars, as normally these biological patrollers are not much different than the cells they pass. But should they come into contact with something suspicious…then pow…the lights and sirens come on and they spring into action. Meet the T cells and B cells, the vanguard of our immune system.
Now meet Joel Pomerantz, an assistant professor in biological chemistry and member of the Hopkins’ Institute for Cell Engineering (ICE) who has been looking at how these specialized immune cells (lymphocytes) become activated. His story might be called “A Tale of Two Baltimores.”
Pomerantz first became interested in the molecular machinery of immune cells while conducting postdoctoral research with David Baltimore at Caltech. “I was fascinated by their ability to interpret diverse signals from the environment and respond during an immune attack in such a wayas to quickly neutralize an invading pathogen without damaging the host.”
His particular focus was a transcription factor called NF-kB, which seems to be a critical activator of immune cell function. As he explains, “you can activate NF-kB through a pathway that doesn’t turn on a lymphocyte. On the other hand, as far as we know, you cannot activate T or B cells without also activating NF-kB.”
However, while the stimuli that activated immune cells were identified, the pathways responsible for activating NF-kB were poorly defined. As a postdoc, Pomerantz developed a novel and straightforward approach to identify such signaling molecules. “Basically, you hook up the promoter region of your gene of interest (NF-kB) to an indicator, like luciferase (the firefly protein). Then you can screen a library to see which genes cause luciferase to glow.” With this method, Pomerantz identified a new signaling molecule called CARD11, which was a critical relay station between the surface receptors that bind bits of bacteria and the proteins that coordinate the response.
In 2003, Pomerantz relocated to Baltimore—the city—to begin the second part of his story. Separately recruited by both the Department of Biological Chemistry and the Immuno-ICE Program, he jumped at the chance to join such a diverse and respected group of faculty.
In the last few years Pomerantz has helped uncover that CARD11 functions as a scaffolding protein that recruits many different signaling molecules into a complex in response to antigen-receptor engagement. “So, when a T cell receptor ‘sees’ something foreign,” he says, “CARD11 is converted from a closed, inactive conformation to an active scaffold that brings together the necessary cofactors which activate NF-kB.”
His most recent work has fleshed out some of the details regarding this conversion. “In short, we have found that CARD11 is kept closed by an inhibitory domain that prevents other signaling proteins from associating with CARD11,” Pomerantz explains. “When a surface receptor recognizes an antigen, it activates kinases that phosphorylate the inhibitory domain and causes it to disengage its interaction with other parts of CARD11and opening up the scaffold.”
“Now, recently, this story has become even more interesting because CARD11 has been directly implicated in the dysregulated NF-kB signaling observed in some cancers,” Pomerantz adds, noting the discovery of CARD11 mutations in a lymphoma called Diffuse Large B Cell Lymphoma. The mutant CARD11 activates NF-kB regardless of whether a surface antigen receptor has been engaged, thus permanently fixing CARD11 in the “on” position and making the B cell think that it is receiving a signal telling it to keep growing. Pomerantz and his group are currently studying the differences by which the normal and hyperactive CARD11 proteins operate, in hopes that they can both advance the understanding of this important signaling molecule and contribute to the development of novel lymphoma therapies. But CARD11 is just one of countless proteins involved in T cell activation, which is why this past September Pomerantz joined forces with other Hopkins immunology experts (see related story) on a multidisciplinary effort to reveal the full T cell deck.
“When a T cell receptor engages a potential antigen at the cell surface, there are several possible outcomes,” Pomerantz notes. “It can secrete chemical signals to recruit other immune cells to eliminate the pathogen, or it can ‘decide’ not to respond, and act as if no antigen has been sensed.” The nature and strength of any given response is in turn governed by a host of factors, including the cell subtype (a helper T cell or killer T cell, for example), that cell’s prior experience with antigens, or the presence of additional environmental signals. “So the global question of our project is how does a T cell process all that data and make the right response?”
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