NK cells are critical for both innate and adaptive immunity. The development of NK cells depends on the interaction between their progenitors and the microenvironment but the regulation of NK cell development is largely unknown. Interestingly, the investigator's preliminary studies indicated that the development of NK cells was severely impaired whereas the numbers of T and B cells remained normal in lymphotoxin-alpha (LT-alpha)-/- mice. Both membrane and soluble LT-alpha are primarily produced by T, B and NK cells while LT receptor is expressed in non-lymphoid cells. Interestingly, LT-alpha-/- mice have an altered splenic architecture and loss of some stromal cells, some of which are continuously regulated by the action of membrane LT through the life while others are developmentally fixed by the action of membrane LT at the fetal stage. Therefore LT-alpha-/- mice provide a unique model to study the mechanisms by which LT regulates NK cell development. 1) They will explore whether LT directly acts through control of NK cell progenitors or whether LT supports a lymphoid microenvironment that is essential for the development of NK cells. A short-term reciprocal transfer of splenocytes will be performed to define the role of the splenic microenvironment on the selection of mature NK cells. A long-term reconstitution with BMC will be performed to further define the role of LT-expressing BMC vs. the microenvironment on the development of NK cells. If LT-expressing cells from wild type mice can restore the number of NK cells in mutant mice, it will be helpful in identifying which individual subsets of lymphocytes is responsible for the development of NK cells. 2) They will also attempt to determine differential requirement of membrane and soluble form of LT in the development of NK cells since LT-alpha-/- mice lack both membrane and soluble LT-alpha. Membrane or soluble LT-alpha activity in wild type mice will be neutralized before or after birth by injecting LTR-Ig fusion protein, which binds to membrane LT-alpha, or anti-LT-alpha antibodies which react with soluble LT-alpha, respectively. Furthermore, this approach will be useful to further define when LT-alpha is essential for the development of NK cells by the specific time frame of administration of the LT-blocking reagents. This study will allow them to develop a mouse model specifically deficient in NK cells for the better understanding of the function and development of NK cells. This study will also help them to elucidate the molecular mechanisms involved in NK-mediated diseases and to design new approaches for manipulation of their immune responses and management of those patients in the future.
| Wu, Q; Sun, Y; Wang, J et al. (2001) Signal via lymphotoxin-beta R on bone marrow stromal cells is required for an early checkpoint of NK cell development. J Immunol 166:1684-9 |
| Wu, Q; Wang, Y; Wang, J et al. (1999) The requirement of membrane lymphotoxin for the presence of dendritic cells in lymphoid tissues. J Exp Med 190:629-38 |
