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.
| Singh, Karnail; Deshpande, Pratima; Li, Guangjin et al. (2012) K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis. Proc Natl Acad Sci U S A 109:E1629-37 |
| Lamar, David L; Weyand, Cornelia M; Goronzy, Jörg J (2010) Promoter choice and translational repression determine cell type-specific cell surface density of the inhibitory receptor CD85j expressed on different hematopoietic lineages. Blood 115:3278-86 |
| Sato, Kayoko; Nuki, Toshiyuki; Gomita, Keiko et al. (2010) Statins reduce endothelial cell apoptosis via inhibition of TRAIL expression on activated CD4 T cells in acute coronary syndrome. Atherosclerosis 213:33-9 |
| Niessner, Alexander; Weyand, Cornelia M (2010) Dendritic cells in atherosclerotic disease. Clin Immunol 134:25-32 |
| Andrews, Nicolas P; Fujii, Hiroshi; Goronzy, Jörg J et al. (2010) Telomeres and immunological diseases of aging. Gerontology 56:390-403 |
| Goronzy, Jorg J; Shao, Lan; Weyand, Cornelia M (2010) Immune aging and rheumatoid arthritis. Rheum Dis Clin North Am 36:297-310 |
| Deng, Jiusheng; Younge, Brian R; Olshen, Richard A et al. (2010) Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 121:906-15 |
| Singh, Karnail; Deshpande, Pratima; Pryshchep, Sergey et al. (2009) ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis. J Immunol 183:8258-67 |
| Li, Guangjin; Yu, Mingcan; Weyand, Cornelia M et al. (2009) Epigenetic regulation of killer immunoglobulin-like receptor expression in T cells. Blood 114:3422-30 |
| Deng, Jiusheng; Ma-Krupa, Wei; Gewirtz, Andrew T et al. (2009) Toll-like receptors 4 and 5 induce distinct types of vasculitis. Circ Res 104:488-95 |
Showing the most recent 10 out of 131 publications
