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T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4(+) and CD8(+) T cells.
Blotnick S; Harvard Univ.
June 30, 1996
Diss Abstr Int [B]; 55(8):3228 1995. Unique Identifier : AIDSLINE

While it has long been known that T lymphocytes infiltrate tumors and atherosclerotic plaques, as well as being found in autoimmune diseases and healing wounds, their role in these normal and disease processes has been poorly defined. In this thesis results are presented that demonstrate that T cells, both in vitro and in vivo, synthesize and release at least two vascular cell growth factors, heparin-binding epidermal growth factor (HB-EGF), a potent mitogen for smooth muscle cells (SMCs) and fibroblasts but not endothelial cells (ECs), and basic fibroblast growth factor (bFGF)-like bioactivity, mitogenic for SMCs, fibroblasts and ECs. The T-cell-derived activities were characterized using heparin-affinity chromatography of T cell conditioned medium (CM) and cell lysate (CL) from peripheral blood lymphocytes (PBL) as well as tumor-infiltrating lymphocytes (TIL) and plaque-infiltrating lymphocytes (PIL), followed by antibody neutralization, Northern analysis and immunohistochemistry. T lymphocytes are divided into two main subcategories, CD4+ helper and CD8+ cytotoxic T cells (CTL). Since their function is different, it made sense to analyze the two subtypes for differential production and release of vascular cell growth factors. A significant difference was found. While helper and cytotoxic T cells were both shown to make message and release bFGF-like bioactivity, only helper cells were found to release HB-EGF protein. Both T cell subtypes make HB-EGF mRNA, but helper cells make 8.5 times as much, as measured using PhosphorImager analysis. bFGF lacks a signal peptide and the mechanism of its release has been a puzzle in cell biology. The prevailing view has been that cell death leads to the release of bFGF from its localization in cytosol. However, we show that T cells whose viability was confirmed by trypan blue exclusion and 51Cr release, release nearly half of their total cellular bFGF-like bioactivity, a much higher percentage than has been found in any other cell type (in SMC there is no detectable release into CM of this peptide). The mechanism of release of T-cell-derived bFGF-like bioactivity remains to be defined. Finally, frozen sections of ovarian and breast tumor tissue, obtained directly from patients undergoing their first surgery for cancer and having never received cancer chemotherapy, were double labeled for the presence of T cells and HB-EGF (or T cells and bFGF). The immunohistochemistry demonstrated that TIL derived from common cancers stained for both growth factors, showing that at least these two potent vascular cell growth factors are synthesized in vivo in tumors. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD95-00019)

Biological Transport CD4-Positive T-Lymphocytes/*METABOLISM CD8-Positive T-Lymphocytes/*METABOLISM Cell Division Cell Survival Cells, Cultured Epidermal Growth Factor-Urogastrone/BIOSYNTHESIS/*METABOLISM Fibroblast Growth Factor, Basic/BIOSYNTHESIS/*METABOLISM Fibroblasts/CYTOLOGY/METABOLISM Heparin/*METABOLISM Human Immunohistochemistry Muscle, Smooth, Vascular/CYTOLOGY/METABOLISM RNA, Messenger/METABOLISM THESIS