DIVERSITY OF T LYMPHOCYTES IN RHEUMATOID ARTHRITIS

Mayo Clinic Coll Of Medicine, Rochester, Rochester MN

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Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a progressive destruction of the joint architecture. CD4+ T cells are likely to have a central role in promoting the synovial inflammation as well as the extraarticular spreading of the disease. Recent studies have led to the model that the global repertoire of CD4+ T cells is important in setting the stage for the inflammatory response. RA patients have several unique features of the CD4+ T cell repertoire. First, the repertoire of CD4+ T cells is influenced by the disease associated HLA-DRB1 polymorphism. Second, RA patients have a different BJ gene segment usage in the naive CD4 population compared to HLA matched controls, suggesting the existence of a genetic risk factor which is involved in BV-BJ gene recombination and/or thymic selection. Third, RA patients carry CD4+ T cells which undergo clonal expansion in vivo. Clonogenic CD4+ T cells recognize self antigens with a wide tissue distribution and are more resistant to apoptosis inducing stimuli. They lack the major costimulatory molecule, CD28, but are dependent on alternate costimulatory signals to proliferate and to escape anergy induction. It is the hypothesis of this proposal that these alternate costimulatory signals facilitate the proliferation and clonal expansion of autoreactive T cells in RA patients and that effector functions mediated by these clonogenic T cells contribute to synovial inflammation and to extra-articular disease. In the first specific aim, we will analyze how the different unique features of the T cell receptor repertoire of CD4+ T cells in RA patients are related and whether thymic selection mechanisms predispose patients to generate CD4+ CD28- autoreactive T cells. In the second specific aim, we propose to identify the costimulatory pathways in CD4+ CD28- T cells. These alternate costimulatory signals may be responsible for the defective downsizing of these T cells in vivo and for their resistance to apoptosis inducing signals in vitro. We propose to analyze pathways which are known to be important in controlling lymphoproliferation, to determine whether these pathways are intact in CD4+ CD28- T cells and to determine how they are regulated by the alternate costimulatory molecules. Finally, we have designed experiments to characterize effector functions of CD4+ CD28- T cells and their dependence on costimulatory signals. In combination, these approaches will allow us to determine how autoreactive CD4+ CD28- T cells are clonally expanded in RA patients and how they function in the rheumatoid inflammation.