This proposal is an examination of the mechanisms involved in antigen-recognition by and activation of human helper T lymphocyte hybridomas specific for the protein antigen Tetanus toxoid (Tet). We have succeeded in producing Tet-specific human T hybridomas with helper activity for semi-autologous B cells in the induction of anti-Tet antibody. We wish to pursue the study of human T helper cell function, using this model, with the following aims: 1. Determination of the signals involved in antigen presentation to T hybridomas: We will map the HLA restricting elements involved in T cell recognition of monocyte-associated antigen and the requirement for Interleukin-1 (Il-1) as a second signal. We will also evaluate the ability of human lymphoblastoid B cell lines to present antigen to T hybrids. Finally, we attempt to tolerize T hybrids on ultraviolet (UV) light-irradiated Tet-pulsed monocytes. 2. Definition of the specificity of Tet-induced helper function of T hybrids: We will determine the ability of Tet-induced T hybrids to provide """"""""bystander"""""""" help for other antigens. We will examine the ability of these helper cells to activate human B cells polyclonally. Finally, we will examine the role of Interleukin 2 (Il-2) in conjunction with T helper hybridomas on the specific and nonspecific activation of B cells. 3. Examination of the antigen-inducible helper factors (THF) produced by these hybrids: We will determine the kinetics and HLA-restriction of THF induction. Once induced, these THF will be characterized as to their molecular weight, their antigen-binding receptors and their DR- and DS-associated molecules. Contribution to these activities by the parental lymphoma used to generate these hybrids will be examined. 4. Assignment of the biological activities of the helper T hybridomas to specific human chromosomes using chromosome loss analysis of man-mouse hybrids: Specifically, we will select clones for antigen recognition, Il-2 production, and THF production and evaluate the human chromosome associated with presence of the function. 5. Documentation of the expression of novel DR-encoded molecules on T hybrids and the recognition of antigen in the context of these determinants: These studies will elucidate the T cell regulatory mechanisms involved in the induction of human antibody synthesis.
| DeFreitas, E C; Sandberg-Wollheim, M; Schonely, K et al. (1986) Regulation of interleukin 2 receptors on T cells from multiple sclerosis patients. Proc Natl Acad Sci U S A 83:2637-41 |
| Koprowski, H; DeFreitas, E C; Harper, M E et al. (1985) Multiple sclerosis and human T-cell lymphotropic retroviruses. Nature 318:154-60 |
| DeFreitas, E C (1985) Human antigen-specific T hybridomas. Behring Inst Mitt :68-74 |
| DeFreitas, E C; Dietzschold, B; Koprowski, H (1985) Human T-lymphocyte response in vitro to synthetic peptides of herpes simplex virus glycoprotein D. Proc Natl Acad Sci U S A 82:3425-9 |
