A proper immune response requires a well-orchestrated interaction among rare antigen-specific lymphocytes and antigen presenting cells, both temporally and spatially. The highly organized lymphoid tissues, lymph nodes (LN) or Peyer's patches (PP), may provide such proper micro- environment. However, the essential components for the development and function of these lymphoid tissues have not been well elucidated. Mice congenitally deficient of lymphotoxin-alpha (LTalpha) manifest impaired splenic architecture and no LN or PP. It appears that the defect in lymphoid structures without intrinsic defect of lymphocytes in LTalpha- /- mice leads to impaired immune responses. It is suggested that the development of splenic microenvironment is regulated by LTalpha- expressing B cells while the organogenesis of LN and PP is mediated by LTalpha-expressing non-T and non-B cells. We will study 1) the regulatory mechanisms of prenatal organogenesis of lymphoid tissues and 2) the consequences of defective peripheral lymphoid tissues in immune responses. To determine whether NK cells, non-T and non-B cells, play an essential role in the formation of lymphoid s*tructures, either reconstitution of LTalpha-/- mice with LT-expressing NK cells or blockage of the function of these cells in normal mice will be performed before or after birth. Furthermore, various immunodeficient mouse models with selected deficiency in either LN, or PP, or different form of LT can be generated by regulating LT activity to the different stage of development. The ability of these mouse models to generate systemic immune response to localized antigens will be subsequently explored to better dissect the functions of individual lymphoid structure or different form of LT. The cellular responses to local antigens in draining LN and the role of PP in gut-associated immunity can be better elucidated. More complete understanding of the development and function of these lymphoid tissues may help us to elucidate the mechanisms of various immunodeficient diseases associated with the defects of lymphoid tissues and provide new approaches for manipulation of immune responses and management of immunocompromised hosts.
