The major objective of this proposal is to define the mechanisms involved in activation of T helper (TH) and T suppressor (TS) cells by type 2 antigens such as polyvinylpyrrolidone (PVP) and pneumococcal capsular polysaccharides. These studies will utilize a method by which PVP-specific TH and TS can be activated in vitro by culturing spleen cells from naive mice with PVP. TH activity is determined by assessing the ability of T cells to provide antigen-specific help to PVP primed B cells for IgG responses while TS activity is determined by the ability of T cells to suppress help provided by the TH. The in vitro method for activation of TH and TS will enable us to determine for the first time the nature of the early signals involved in T cell activation by a type 2 antigen. Moreover, since TH can also be activated in vitro using the T dependent (TD) antigen, PVP-HRBC, the mechanisms by which type 2 and TD antigens activate TH can be directly compared. Some questions to be addressed will include: studies of the role and function of antigen presenting cells (APC) in TH vs. TS activation, the requirement for cell proliferation and the role of lymphokines such as interleukins 2 and 4 in TH and TS activation. In addition, because PVP-specific TH have some properties which distinguish them from the major subset of TH activated by most classical TD antigens, another major goal will be to determine whether PVP- specific TH can be categorized (by assessment of lymphokine secretion and expression of CD45R molecules) as belonging to either of the major TH subsets, THl and TH2, or whether they are a distinct TH subset. We will also attempt to obtain enriched populations of PVP-specific T cells to assess the expression of T cell receptor molecules by these cells and to obtain TH lines and clones to determine whether long-term in vitro growth might influence the properties of these TH. Type 2 antigens include most bacterial polysaccharides such as pneumococcal capsular polysaccharides. As many currently available bacterial polysaccharide vaccines are poorly immunogenic in children and immunocompromised individuals, the development of means to increase the immunogenicity of such antigens is of obvious importance. Our studies are aimed at determining how type 2 antigens activate TH and understanding the nature of the early signals that result in TH as opposed to TS activation. Information derived from these studies could thus be relevant for developing immunization protocols in which the selective activation of TH and/or prevention of TS activation would result in increased immune responses to these antigens. In a more general sense, the ability to selectively activate TH and reduce TS activity could also be important in increasing tumor immunity and for treating patients with immunodeficiency diseases.
| Braley-Mullen, H; Milligan, G N; Van Buskirk, A M (1994) Requirement for B cell-derived immunoglobulin for Th activation by the type 2 antigen polyvinylpyrrolidone. Int Immunol 6:805-15 |
