Neuropeptide Y (NPY) stimulates cytokine production from antigen-presenting cells, but inhibits it from T cells.

A stress hormone sends mixed signals to immune cells, according to a study on page 1527. Wheway and colleagues show that neuropeptide Y (NPY) activates antigen-presenting cells (APCs) but shuts off T cells. If correctly sequenced, these activities would both turn on and then limit certain immune responses.NPY is an abundant neuropeptide that is released from sympathetic nerve endings. In the brain, NPY regulates physiological and emotional processes, including metabolism, heart rate, and depression. NPY is also produced by activated immune cells and has been shown to dampen cytokine production by macrophages and inhibit the killer activity of natural killer cells.

The effects of NPY on T cells, however, have been controversial. Treatment with NPY ameliorates autoimmune disease in a mouse model of multiple sclerosis, suggesting a suppressive effect on the disease-inducing T helper (Th)-1 cells. But mice lacking the major lymphoid receptor for NPY (Y1) were protected from colitis, another Th1-driven autoimmune disease, suggesting that NPY signaling normally activates Th1 cells.

The study by Wheway and colleagues helps clear up these conflicting reports. They show that NPY indeed inhibits Th1 responses, as T cells from Y1-deficient mice produced more interferon (IFN)-γ than wild-type cells when stimulated in vitro. When transferred, Y1-deficient T cells were hyperactive and triggered more severe colitis in recipient mice than did wild-type T cells.

However, the receptor-deficient mice themselves were resistant to T cell–mediated colitis when treated with an intestinal irritant. The defect was traced to APCs, which could not be activated in the absence of NPY signaling. APCs from the Y1-deficient mice failed to produce the Th1-promoting cytokines interleukin-12 and TNF and could not activate naive T cells. These mice were thus protected because the T cell response never got started.

How is a T cell response ever mounted if the same signal that turns on the APC turns off the T cell? The authors suspect that it comes down to timing. The expression of the Y1 receptor on T cells might be induced only after activation, thus providing a negative feedback loop that keeps activated T cells from running amok. The authors now plan to study NPY-induced signaling in different cell types to determine how the same molecule tells some cells to go and others to stop.