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Mobilizing Cytokine Receptor Key Step in Defense Coordination
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Mobilizing Cytokine Receptor Key Step in Defense Coordination
Recruitment of Interferon Gamma to Immunological Synapse Decides T Cell FateWhen the body's immune defense team takes the field, there are choices to be made. Like fresh recruits filling out the defensive line, inexperienced T cells must quickly identify the offense and initiate the proper neutralizing play. Depending on whether the threat is bacterium or virus, cancer cell or cat dander, naive T cells read the signals and make a snap decision to transform into cells that either promote an inflammatory response or boost antibody production. A bad choice can blow the game, resulting in autoimmune disease or uncontrolled infection.
Immunological synapses signal T cell fates. Differentiation of T helper cells begins when a dendritic cell (DC) brings MHC proteins loaded with antigen (Ag) to a T helper progenitor cell (Thp). When antigen and T cell receptor (TcR) meet, recruitment of adhesion and signaling molecules leads to formation of the immunological synapse. Inclusion of the interferon gamma receptor (IFNR) at the synapse favors the development of T helper type 1 cells, while its exclusion under the influence of IL4 leads to T helper type 2 production. The synaptic localization of the interferon gamma receptor may allow the T cell to sense minute amounts of the cytokine (dark pink circles) produced nearby.
Recent work from the HSPH lab of Laurie Glimcher characterizes a new and important role for the cell contact structure called the immunological synapse in the early choice of defense strategy. According to the study, T helper cell differentiation down one pathway or the other depends on the physical movement of a key cytokine receptor into or out of the area of cell-cell contact. The study appears in Nature online and in the Sept. 30 print edition.
"The importance of this work is not only what it says about lineage commitment for the T helper cell, but also that this is the first indication that the immunological synapse plays a role in T cell differentiation," said Glimcher, the Irene Heinz Given professor of immunology at HSPH and HMS professor of medicine.
Points of Contact
The word synapse conjures up visions of nerve cells in intimate contact conveying private messages via secreted signaling molecules. But synapses also occur between cells in the immune system. At the immunological synapse, antigen receptors and adhesion molecules glue T cells to accessory cells bearing stimulatory antigens. Like a team huddle, this cozy arrangement lets the cells take their time passing signals to each other over the short distance between their juxtaposed membranes.
By watching the movements of interferon gamma receptors on progenitor T cells, Roberto Maldonado and Laurie Glimcher discovered a new role for the immunological synapse in cell differentiation. (Photo by Steve Gilbert)
Young T cells that encounter their first antigen have two possible fates. When they form a synapse in the presence of interferon gamma, they become T helper type 1 (Th1) cells and stimulate inflammatory responses. If interleukin-4 (IL4) is present when they meet an antigen, the cells turn into T helper type 2 (Th2) cells that promote B cell activation and antibody production. Separate environmental cues that trigger T helper differentiation were well understood thanks to previous work from the Glimcher lab and others, but the puzzle remained about how T cells integrated information on antigen and cytokine levels to reach a differentiation decision.
Deciding Cell Fate
Glimcher was already wondering several years ago whether the earliest stages of antigen contact and synapse formation could cause a gathering of cytokine receptors into the synapse that would seal the cell's fate. "Everyone was looking at the role of the immunological synapse and antigen receptor in immune cell activation," Glimcher recalled, "but no one was thinking about cytokine receptors or about a function for the immunological synapse in cell fate decisions." At a meeting, she chatted with a potential postdoc and found they shared a common interest in the question. A year later, when Roberto Maldonado showed up at her lab as a new research fellow, they were both still pondering the idea and he decided to address it.
| "The importance of this work is not only what it says about lineage commitment for the T helper cell, but also that this is the first indication that the immunological synapse plays a role in T cell differentiation." |
The next two years sped by as Maldonado searched for evidence that the recruitment of the interferon gamma receptor to the immunological synapse actually had a function in differentiation. He examined T cells from two strains of mice, one that was prone to Th1 differentiation and one that more readily developed Th2 cells. He found that the mice tending to go down the Th1 pathway were much more likely to have interferon gamma receptors located in the immunological synapse than the Th2-prone mice.
Finally, the researchers asked whether IL4 treatment, known to push cells away from the Th1 pathway and toward Th2, would affect the distribution of the interferon receptors. To his surprise, Maldonado said, treating cells with IL4 completely prevented interferon receptors from entering the immunological synapse. "That was kind of a crazy experiment," he remembered. "There wasn't any dogma or experiment already out there that could lead us to think this could happen." But the result held up when Maldonado used T cells from mice deficient in the IL4 signaling protein Stat6 and showed that the response to IL4 was lost.
The clustering of interferon gamma receptors in the immunological synapse could ensure that T cells get the message even when very small amounts of interferon gamma are produced nearby during cell coupling. "If there's localized secretion of interferon, then the receptor is right there, and the cell can go on its merry way towards Th1 differentiation," explained Glimcher. "Cytokines are known to act locally, and that's where the immunological synapse could be like a neuronal synapse. Everything is focused right at the point of secretion."
Going beyond the immune system, Glimcher speculates that controlled colocalization of receptors at synapses or at other sites of cell contact might be a general strategy for controlling cell fate in many cell and tissue types, including neurons, muscles, adipocytes, and endocrine tissues.
For now, the researchers have no idea how the interferon gamma receptor is physically moved to the immunological synapse and how signaling through the IL4 receptor can keep it out. Those questions await more in-depth studies of receptor biomechanics that Maldonado plans to tackle next.
--Pat McCaffrey