Defense Date

1993

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

Harry Douglas Bear

Abstract

Transforming growth factor-β1 (TGFβ) is a peptide cytokine implicated in control of growth, adhesion, and differentiation of cells in numerous tissues. TGFβ has potent inhibitory effects on many lymphocyte responses; we also found that TGFβ could inhibit in vitro generation of tumor-specific CTL. Suppression was largely reversed with exogenous IL-2. Proliferation of memory-stage CTL clones was also inhibited by TGFβ, while the upregulation of cytotoxicity was not inhibited by TGFβ. These studies suggested that TGFβ limited anti-tumor CTL responses via both an indirect effect on IL-2 production, and by a direct effect on proliferation of memory CTL.

In CTLL-2 cells, TGFβ inhibited IL-2-dependent DNA synthesis and cell growth as early as 24h after addition. TGFB inhibited IL-2-dependent surface IL-2Rα expression 24h after treatment, while cells remained 100% IL-2R+ up to 48h after treatment. TGFβ inhibited c-myc mRNA expression as early as 1h after treatment, suggesting that TGFβ may inhibit T cell growth by either altering signal transduction through the IL-2R, or by otherwise inhibiting early gene expression events triggered by IL-2 binding.

TGFβ treatment also resulted in morphologic changes and increased adherence in 50% of CTLL-2 cells. Adherence required the presence of fetal calf serum and could be largely blocked by RGDS peptides. Under these conditions, de novo surface expression of CD8α and CD8β was observed and these cells rapidly accumulated mRNA encoding both CD8α and β chains, to a level 4-fold greater than control.

Treatment of CD4-CD8- thymocytes with IL-2 + TGFβ similarly induced high levels of de novo CD8α expression on one-third of cells, while few thymocytes treated with IL-2 alone became CD8α+. CD8 expression in mature, peripheral CD8+ cells was not influenced by TGFβ. These data suggest that TGFβ has both positive and negative regulatory effects on the expression of molecules important for T lymphocyte growth, differentiation and function, and TGFβ may be a physiologically important cytokine for initial expression of CD8 in the thymus.

Comments

Scanned, with permission from the author, from the original print version, which resides in University Archives.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

11-29-2017

Included in

Microbiology Commons

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