It has become increasingly clear that the process of thymic education involves complex interactions between developing T lymphocytes and various stromal components of the thymus. In spite of the significant effort put forward understanding these interactions, the events which mediate this process remain ill defined. Most studies aimed at addressing these issues have been hampered, to a large extent, by the complexity of the thymus. This system can be best simplified by characterizing cell lines that function similarly to cells interacting in the thymus. Therefore, during the previous two years of funding we have established lines of T lymphocyte precursors and of cells inducing positive and negative selection. The primary goal of our research has been the definition of accessory cells that drive T lymphocyte development in the thymus. Their identification directly bears upon our understanding of mechanisms forming the T lymphocyte repertoire. Since we have shown that cultured fibroblasts induce positive selection, nd that peripheral B cells clonally delete auto-reactive thymocytes, we can no longer support hypotheses of thymic selection that are built around the premise of unique thymic AC. Therefore, models have to be favored which explain the paradox of thymic education on the basis of conventional ab-T lymphocyte interactions similar to those in the periphery. Thus, this research grant has been used to gain the information and to produce the tools to will be crucial to define how positive selection creates the repertoire of T lymphocyte specificities. More specifically it is proposed to characterize positive selection on fibroblasts, to determine how peptidic antigens influence the formation of the TCR repertoire, and to define peptides involved in positive selection. Thus, these studies are designed to learn how TCR-MHC interactions create the T lymphocyte repertoire.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD026841-04
Application #
2200110
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1991-02-01
Project End
1998-01-31
Budget Start
1994-02-10
Budget End
1995-01-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Irion, S; Berg, R E; Staerz, U D (2000) A physiological ligand of positive selection is seen with high specificity. J Immunol 164:4601-6
Staerz, U D; Lee, D S; Qi, Y (2000) Induction of specific immune tolerance with hybrid antibodies. Immunol Today 21:172-6
Berg, R E; Irion, S; Kattman, S et al. (2000) A physiological ligand of positive selection is recognized as a weak agonist. J Immunol 165:4209-16
Berg, R E; Princiotta, M F; Irion, S et al. (1999) Positive selection of an H2-M3 restricted T cell receptor. Immunity 11:33-43
Staerz, U D; Qi, Y (1999) Treatment of an autoimmune disease with ""classical"" T cell veto: a proposal. J Clin Immunol 19:195-202
Qi, Y; Staerz, U D (1998) Specific inhibition of CD4+ T lymphocytes by a hybrid antibody. Nat Biotechnol 16:271-5
Princiotta, M F; Lenz, L L; Bevan, M J et al. (1998) H2-M3 restricted presentation of a Listeria-derived leader peptide. J Exp Med 187:1711-9
Qi, Y; Berg, R; Singleton, M A et al. (1996) Hybrid antibody mediated veto of cytotoxic T lymphocyte responses. J Exp Med 183:1973-80
Candeias, S; Hardy, R R; Li, Y S et al. (1994) T cell receptor V beta 8.2 gene germ-line transcription: an early event of lymphocyte differentiation. Eur J Immunol 24:3073-81