The goal of this proposal is to investigate the role of CD1-restricted T cells in autoimmune disease using systemic lupus erythematosus (SLE) is a model. Pathogenic autoantibody production against non peptides in SLE is dependent upon T cell help, thus SLE represents an immunological enigma according to the existing paradigm of T cell recognition of peptide-only antigens. CD1 antigen presentation of non-peptide molecules in SLE produce IL-4 and recognize autoantigen presented by B cells in the context of CD1. We hypothesize that CD1-restricted T cells in SLE recognize non peptide antigens and provide help for B cells to produce autoantibodies against the same antigen, thereby contributing to the pathogenesis of autoimmune disease. To test this hypothesis we first propose to ascertain the restricting element and cytokine patter of CD1- restricted autoreactive T cells in SLE by deriving T cell lines and clones from the cutaneous lesions and blood of patients and compare them to T cell lines derived from healthy donors. Second we will investigate whether the cognate interaction of CD1c-restricted autoreactive T cells and CD1c+ B cell deletion or activation. We will also investigate the role of CD1+ antigen presenting cells (APCs) in directing CD1 peptide antigens which stimulate CD1-restricted autoreactive T-cell responses. This final goal will be achieved by purifying the CD1c ligand from a soluble endogenously loaded CD1c and use the ligand to stimulate CD1-restricted autoreactive T-cells. The studies within this proposal should provide a comprehensive understanding of the interaction between T-B cells in the generation of immunoglobulin to non-peptide antigen in SLE. Furthermore, the studies should also provide a more complete definition of CD1c+B cells, a population of B cells that arises early in the development of the immune system, but whose function remains unknown. Finally, we anticipate that our findings will be useful in establishing new mains of treating autoimmune disease.
| Garcia, V E; Quiroga, M F; Ochoa, M T et al. (2001) Signaling lymphocytic activation molecule expression and regulation in human intracellular infection correlate with Th1 cytokine patterns. J Immunol 167:5719-24 |
| Sieling, P A (2000) CD1-Restricted T cells: T cells with a unique immunological niche. Clin Immunol 96:10-Mar |
| Sieling, P A; Porcelli, S A; Duong, B T et al. (2000) Human double-negative T cells in systemic lupus erythematosus provide help for IgG and are restricted by CD1c. J Immunol 165:5338-44 |
