How Interleukins Keep the Immune System in Balance

The body’s immune response fights against infectious disease and safeguards against future infections. However, it can also attack the body itself, causing autoimmune diseases. A study published Friday in Science Immunology looks into a possible mechanism that may maintain or disrupt this ‘balancing act’ of the immune system.

A key player in this mechanism is the T follicular helper (Tfh) cell. These cells are essential in vaccination responses, but they can be harmful actors in an autoimmune disease like lupus. The new study shows that Tfh development is affected by the interplay of two interleukin signaling proteins, IL-6 and IL-2. This interplay may be important for a balanced immune system.

“It is well-known that abnormal expansion of Tfh cells correlates with disease severity in systemic lupus erythematosus patients,” says senior author André Ballesteros-Tato of the University of Alabama at Birmingham. “Unfortunately, there are currently no therapies to selectively deplete Tfh cells in vivo. Based on our data, it is tempting to speculate that blockade of IL-6 with IL-6-neutralizing antibodies—in combination with recombinant IL-2 administration—will synergize to efficiently prevent Tfh cell responses in autoimmune patients, thereby avoiding the production of self-reactive antibodies.”

To develop, Tfh cells react with antigens presented outside of B cell follicles in the lymph nodes or spleen. The activated Tfh cells then move into the follicles, where the Tfh cells interact with B cells to produce a germinal center—a factory that multiplies and transforms B cells into high-specificity, antibody-producing cells.

But as Tfh cells become germinal center–Tfh cells, they need sustained T-cell receptor stimulation to maintain the germinal center–Tfh state. Yet that same stimulation is known to induce expression of IL-2 and its receptor, which together should create a feedback loop of IL-2 signaling that is known to inhibit Tfh cells. Therefore, Ballesteros-Tato and colleagues sought to understand how Tfh cells evade this potent inhibition. Using a model of influenza infection in mice, they found that IL-6 protects Tfh cells from the deleterious effect of IL-2 by interrupting the feedback loop.

Altogether, these results have identified a regulatory mechanism that controls the generation of germinal center–Tfh cells. Instead of one interleukin or another controlling the response of Tfh cells in an on–off fashion, IL-6 signaling fine-tunes the threshold of IL-2 responsiveness; thus, the relative levels of the two interleukins determine the fate of the Tfh cells.