Nature Immunology pp 1045 - 1051

Immune cells travel throughout the body sniffing for hints of infection or injury. Circulating immune cells respond to chemical cues that tell them to stop traveling and exit the bloodstream, which they accomplish by rapidly altering their ability to stick to other cells. In the October issue of Nature Immunology, Japanese researchers show that lymphocytes in mice that do not have the protein RAPL have defective brakes and are unable to adhere to tissues and follow the body's traffic signals. Thus, these cells fail to arrive at locations necessary for generating immune responses.

So how do cells stick in the first place? Adhesive proteins known as integrins are expressed on the cell surface. An intracellular protein called Rap1 acts as a switch that controls the stickiness of the integrins, turning them on and off. Rap1 itself, though, is instructed through RAPL, officially known as 'regulator of cell polarization and adhesion enriched in lymphocytes'. RAPL sets Rap1 in the "ON" state, thereby inducing the integrin molecules to expose their sticky ends. In the "OFF" state, integrins mask these sites, which allows cells to continue their bloodstream journey. Although RAPL-deficient mice have normal numbers of bloodstream lymphocytes, lymphoid tissues such as their lymph nodes and spleen were vastly under-populated, illustrating the transit defect in these mice. The cells in these mice also displayed migration defects when they were responding to inflammatory signals. Hence, although our inner signals are not red, we can think of RAPL as being crucial for getting immune cells to obey the body's STOP signs.