A complex series of cellular interactions, including both helper cell and suppressor cell pathways, influences the generation of cellular immune responses. This proposal is directed at defining, on a molecular level, the antigenic requirements for the induction of the cellular interactions which regulate the CTL response. The information gained from the proposed project may lead to means of efficient clinical intervention, summons the induction of specific suppression in cases of autoimmune disorders and organ or tissue transplants, and the specific enhancement of responses in cases of malignancies or viral infections. Previous studies using class I major histocompatibility complex (MHC) antigens have allowed the demonstration of Ly1+,2,3- helper and suppressor T cells for CTL responses. Until recently however, it has been difficult to precisely define these regulatory events because the antigens responsible for the CTL response, the MHC antigens, are integral membrane proteins and thus are difficult to manipulate. In order to define the molecular events triggering one pathway in prefence to the other purified membrane antigens inserted into liposomes will be used. Purified H-2Kk and I-A antigens, cloned responding T lymphocytes, monoclonal antigen-presenting cell lines, and cloned I-A genes will be utilized to address such issues as: whether the same forms of antigen are recognized by both helper and suppressor cells (e.g. native vs. APC modified or conformational determinants); the role of MHC intramembranous and intracytoplasmic domains for stimulation of responses; the kinetics of activation of suppression vs. help; the nature of the association between antigen and Ia; and Ia structure and function correlations using biochemical analysis as well as recombinant DNA.
| Flaherty, L; DiBiase, K; Lynes, M A et al. (1985) Characterization of a Q subregion gene in the murine major histocompatibility complex. Proc Natl Acad Sci U S A 82:1503-7 |
