Recent studies demonstrate two distinct subpopulations of CD4-8- T lymphocytes, one expressing T cell receptor alpha-beta (TCRalpha beta) and the other bearing the newly described TCRgamma-delta. Preliminary results suggest that these CD4-8- T cells perform a role in immune responses to microbial pathogens, and also in the autoimmune pathogenesis of diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This proposal will focus on mechanisms by which CD4-8- T cells mediate specific immune recognition and will build upon preliminary work showing that non-MHC encoded CD1 glycoproteins may act as antigen presenting or self recognition molecules for T cells of this phenotype. The studies propose to: 1) demonstrate quantitative abnormalities of CD4-8- T cells in RA and SLE using flow cytometry; 2) establish CD4-8- T cell lines and clones from normal subjects and from patients with SLE and RA; 3) analyze the effector capabilities of CD4-8- T cell lines including production of lymphokines and lysis of CD1+ target cells; 4) construct a panel of CD1 expressing antigen presenting B cells by DNA transfection, and test their ability to present microbial antigens to CD4-8- T cells; 5) determine the repertoire of TCR V genes expressed by CD4-8- T cells of normal subjects and patients with RA and SLE by a combination of molecular and serologic techniques; and 6) reconstitute the TCR of a CD1a reactive T cell clone by DNA transfection into a TCR- recipient T cell line to prove whether or not recognition of CD1 is mediated by the TCR. These studies will help to determine the function of CD4-8- T cells and CD1 molecules in specific immunity to infection, and may also have direct bearing on disease related mechanisms in RA and SLE. The work will be performed in the Laboratory of Immunochemistry at the Dana-Farber Cancer Institute under the sponsorship of Dr. Michael Brenner. This laboratory is among the best locations for pursuing molecular work on the T cell receptor, and the surrounding Harvard Medical Area provides an unusually stimulating and advanced center for motivating young investigators. Cosponsorship by the applicant's department chairman, Dr. K. Frank Austen, will assure a high level of overall academic excellence in the applicant's training. By executing the studies described in this proposal the applicant will acquire expertise in a wide variety of techniques in cellular and molecular biology. He then plans to use these skills to continue his studies of T lymphocyte function in immunity and autoimmunity as an independent investigator.
| Beckman, E M; Melian, A; Behar, S M et al. (1996) CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family. J Immunol 157:2795-803 |
| Subauste, C S; Chung, J Y; Do, D et al. (1995) Preferential activation and expansion of human peripheral blood gamma delta T cells in response to Toxoplasma gondii in vitro and their cytokine production and cytotoxic activity against T. gondii-infected cells. J Clin Invest 96:610-9 |
| Porcelli, S A (1995) The CD1 family: a third lineage of antigen-presenting molecules. Adv Immunol 59:1-98 |
| Behar, S M; Porcelli, S A (1995) Mechanisms of autoimmune disease induction. The role of the immune response to microbial pathogens. Arthritis Rheum 38:458-76 |
| Behar, S M; Porcelli, S A; Beckman, E M et al. (1995) A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells. J Exp Med 182:2007-18 |
