"Our results show that in the very early stages of T helper cell commitment, there is physical movement of receptors for the cytokine interferon-gamma into the immunological synapse, and this movement seems to determine the ultimate developmental fate of the cell," said Glimcher, Irene Heinz Given Professor of Immunology in the Department of Immunology and Infectious Diseases.

The work, published in Nature on September 30, reveals a new role for the immunological synapse as the place where developing T helper cells integrate information about antigen and cytokine levels to produce the best possible defense against each new threat.

Differentiation of T helper cells begins when an antigen-loaded accessory cell first makes contact with the antigen receptor on the T cell. The juxtaposition of the two immune cells causes the organization of adhesion and signaling molecules into the immunological synapse, a Velcro-like patch that keeps the cells stuck together while the T cell receives its marching orders. Once the immunological synapse is established, the progenitor cells have only two possible fates. If the cytokine interferon-gamma is floating around, they differentiate to T helper type 1 cells that cause inflammatory immune responses. But if interleukin-4 (IL4) is in the area, the T cells transform to T helper type 2 cells and support antibody production.

Glimcher’s idea was that the cytokine signals regulating cell differentiation might be passed via the immune synapse right alongside the antigen receptor. A research fellow in her lab, Roberto Maldonado, used a confocal imaging microscope to shoot movies of T cells from mice as they made their first contact with antigen-presenting cells. In collaboration with Darryl Irvine at MIT, Maldonado captured the action as the T cells responded to antigen by spiking their intracellular calcium concentrations. Soon, he saw the fluorescently labeled T cell antigen receptor move into the gathering immunological synapse, followed closely by the interferon-gamma receptor. Maldonado checked the movement of several other cytokine receptors but did not see the same localization pattern.

To prove that the interferon gamma receptor movement was a first step in differentiation, Maldonado showed that T cells from a mouse strain that made lots of Th1 cells were much more likely to have interferon-gamma receptors located in the immunological synapse than T cells from a different, Th2-prone strain. And exposing the T cells to IL4, which inhibits Th1 formation and encourages Th2, completely prevented the interferon receptor from entering the immunological synapse.

Maldonado and Glimcher are eager to understand the biomechanics of how the interferon-gamma receptor moves to the immunological synapse, and how IL4 can keep it out. Their suspicion is that the dynamic regulation of receptors as a way to control cell fate decisions will be a recurring theme for many differentiating cells, both inside the immune system and out.

--PM