Rolling lymphocytes do not gradually decelerate before stopping.

ALON/MACMILLAN

Lymphocytes reach out a retractable hook to stop on a dime when necessary, based on findings from Revital Shamri, Ronen Alon (Weizmann Institute of Science, Rehovot Israel), and colleagues.

Lymphocytes and other white blood cells roll along vessel walls scanning for immobilized chemokine signals that tell them where to stop on the endothelium. They only stop once their integrins, which are otherwise kept bent and inactive, are properly activated. As arrest requires dramatic adhesion changes, most scientists assumed that rolling allowed signals to accumulate and globally activate integrins, thus decelerating and eventually stopping the rolling cell. In some settings, such as neutrophils rolling on E-selectin, deceleration lasts several minutes. But the new findings show a much more abrupt stop of lymphocytes on the endothelium.

Rolling was not even necessary for neutrophils to stop. Endothelium-bound chemokines needed less than 0.3 s in contact with the neutrophil integrin LFA-1 to trigger its extension. Extended LFA-1 can more easily reach its endothelial ligand (such as ICAM-1) but does not bind it tightly. To latch on, the group shows, the integrin must encounter its ligand less than 0.5 s after seeing the initial chemokine signal.

“The integrin ligand should be very close to the chemokine,” says Alon. “If cells see sporadic chemokine spatially misorganized [with respect to the integrin's ligand], it results in an abortive activation signal.” The hook is quickly retracted, and the cell rolls on. Integration of chemokine signaling is not necessary, so cells stop precisely where a signal lies, rather than rolling and collecting signals over a long path.

Recent structural data fit well with the findings. Integrin structures reveal “an intermediate state when integrin is extended, primed, but not fully committed,” says Alon. Intracellular signals, as might be generated by rapidly activated chemokine receptors on the lymphocytes, get integrins to that state by what is known as inside-out signaling. “For proper acquistion of high affinity,” says Alon, “the ligand must do the next half.” Since the ligand must act quickly, Alon suggests that “the integrin and chemokine machineries are preformed on the lymphocyte surface.”

Reference:

Shamri, R., et al.
2005
.
Nat. Immunol.
6
:
497
–506.