Project: Research project

Project Details


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
Effective start/end date7/1/916/30/96


  • Immunology


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