The diversity of T cell responses has been found to be relatively restricted for a given antigen. For example, T cells specific for a model antigen, pigeon cytochrome c, express the same T cell receptor (TCR) alpha-chain variable (V)-region (Valpha11), and mainly express the same beta-chain (Vbeta3). In addition, the most diverse part of the receptor is the junction between the rearranging gene elements, and for this response, as well as all others examined, these V(D)J junctional sequences are highly conserved. This type of defined immune response may be a model for the study of autoimmune diseases such as multiple sclerosis or rheumatoid arthritis. Previous work has shown that the T cell response to myelin basic protein (MBP) resulting in Experimental Allergic Encephalitis (EAE, a model of multiple sclerosis), is indeed restricted with respect to the TCR gene elements expressed within the population. Moreover, this autoimmune response can be regulated by prior immunization of an animal with MBP specific T cell clones, or with an oligopeptide with the same sequence as various portions of the conserved TCR beta-chain. Such treatments prevented the onset of EAE in animals subsequently challenged with MBP. The implication of these results is that the immune responses may be subject to modulation using TCR sequences known to be expressed on particular antigen specific T cells. Although successful, these efforts raise many questions about the mechanisms of immunomodulation. Since it is difficult to specifically monitor the antigen-reactive T cell population in vivo, it is not clear whether the protection occurs via deletion or the induction of anergy, and whether the immunomodulation is carried out by T cells, antibodies, both or neither. We have made transgenic (tg) mice, in which rearranged alpha- and beta-chain genes have been introduced into the mouse germline. These mice are essentially monoclonal for T cells expressing pigeon cytochrome c-specific receptors. In order to create a mouse with a large proportion of its T cells expressing a common idiotype and specific for a defined antigen, and the remaining proportion comprised of normal T cells, we will reconstitute the immune system of irradiated mice with mixtures of bone marrow from normal and tg mice. After regimens of immunomodulation, we will challenge these mice with the specific antigen and measure the in vivo or in vitro response. We will then directly investigate the mechanisms of this immunomodulation.
