Abstract

Monoclonal antibodies (mAb) to MHC class II molecules (anti-class II mAb) have been well described in their ability to inhibit T cell activation. The most current model is that anti-class II mAb interfere directly with the T cell receptor-major histocompatibility complex crosslinking which is necessary for T cell activation. The anti-CD3 mAb, OKT3, is an MHC class II molecule-independent mitogen which causes T cell activation by direct ligation of the TCR-CD3 complex. OKT3 and a panel of anti-class II mAb were used to dissect the individual roles played by these two receptors in activation and inhibition of peripheral blood mononuclear cells. In this study, it is shown that the inhibition of OKT3-dependent T cell activation correlates with metabolic activation of antigen presenting cells. In contrast, inhibition of lectin- and superantigen-mediated T cell activation may occur without activation of antigen presenting cells. It is also shown that the anti-class II mAb that inhibit OKT3-mediated T cell activation also induce tyrosine phosphorylation, metabolic activation of adherent mononuclear cells, heterotypic cell aggregation, and formation of multinucleated giant cells. One mAb, 417, was previously shown by Dr. G. A. Molinaro to inhibit lectin-mediated T cell activation, but was unable to inhibit OKT3-mediated activation. All other anti-class II mAb which were tested inhibit all forms of T cell activation. Thus, it is also shown that 417 does not induce tyrosine phosphorylation or metabolic activation, and that the inability of mAb 417 to inhibit OKT3 activation is not dependent on the IgM isotype or MHC subclass specificity. Using cell culture inserts, solid-phase anti-class II mAb are shown to induce the release of a soluble inhibitory factor from mononuclear cells. Finally, flow cytometry, fluorescent microscopy, and gel electrophoresis were used to show that ligation of MHC class II molecules on antigen presenting cells induces activation-dependent apoptosis of T cells. The author proposes that antigen presenting cells may be the discriminating factor between activation and deletion in the avidity models of T cell selection and peripheral tolerance.

LLU Discipline

Microbiology and Molecular Genetics

Department

Microbiology, Molecular Biology and Biochemistry

School

Graduate School

First Advisor

Giuseppe A. Molinaro

Second Advisor

Amnon Altman

Third Advisor

Lora Green

Fourth Advisor

David Hessinger

Fifth Advisor

John Sands

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level

Ph.D.

Year Degree Awarded

1995

Date (Title Page)

12-1995

Language

English

Library of Congress/MESH Subject Headings

T-Lymphocytes Monocytes: Signal Transduction: Indicators and Reagents: DNA

Type

Dissertation

Page Count

xvi; 181

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

Download

Share

COinS