Regulated actin and microtubule dynamics are critical components of immune cell functions, as genetic and pharmacological inhibition of cytoskeletal dynamics renders Immune cells incapable of performing many of their effector functions. Actin assembly regulation is a complex process that involves many proteins including actin nucleators as well as their activators and effectors. The exact role and distinct modes of actin nucleation have yet to be elucidated in immune cells and how these processes affect immune cell functions. Activators of actin nucleation including cortactin have been largely studied in cells of non-hematopoietic lineage. However, in cells of hematopoietic lineage, adhesion, migration and actin cytoskeletal dynamics are highly regulated to prevent unwarranted immune cell functions. Arp2/3 and formins are two distinct actin nucleators and HS1 is a known activator of Arp2/3, yet their roles in immune cell functions and in particular natural killer (NK) cells remains incompletely understood. In addition, microtubule dynamics are required for NK-mediated cytolysis and recently it has been observed that formins play a role in microtubule dynamics. Microtubules play a distinct role in the delivery of cytolytic granules to the lytic synapse and formins play a critical role in linking the actin and microtubule cytoskeletons. Therefore, this proposal will examine the roles of Arp2/3 and formins in cytoskeletal dynamics, both actin and microtubule, in distinct NK functions.

RELEVANCE (See instructions): NK cells are capable of promoting bone marrow rejection and as well as engraftment. NK cells also elicit potent anti-tumor effects. The clinical relevance of NK cells has begun to be appreciated, and new clinical studies utilizing NK cells for the treatment of cancer patients have begun to be met with modest success. A fuller understanding of how NK cells interact with target cancer cells will advance NK immunotherapy.