Lymphocyte chemoattractant factor (LCF) induces CD4 cell activation following interaction with the CD4 antigen
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Abstract
The mechanism by which unsensitized lymphocytes are sequestered and acitvated within tissue is not clearly understood. A relationship between motility and cell cycle progression has been established for several lymphocyte growth factors. In this thesis we investigated the mechanism by which a lymphocyte chemoattractant factor (LCF) induces cellular motility, and whether this lymphokine has the capacity to initiate cell activation. Using monoclonal antibodies and several different lymphocyte and monocyte cell lines, it was determined that LCF elicits its migratory effect via interaction with the CD4 antigen. The effects of LCF stimulation were completely blocked by co-incubation with Fab fragments of the anti-CD4 antibody. LCF also induced a migratory response in murine L3T4-, CD4+ T cell hybridoma cell lines.
When normal human CD4+ lymphocytes and monocytes were incubated with LCF for 24 hours, a marked upregulation of two activation dependent membrane determinants were observed. LCF induced the expression of the interleukin 2 receptor and HLA-DR antigen in lymphocytes, and an upregulation of HLA-DR in monocytes. These findings indicate that LCF, via its interaction with CD4, can act as a growth factor, and induce activation in resting lymphocytes and monocytes. To determine the mechanism by which LCF induced cellular activation, we investigated changes in second messengers utilized in signal pathways. Following LCF stimulation of normal human lymphocytes, we observed a rise in intracellular calcium along with an increase in the production of inositol-trisphosphate. Similar results were obtained when CD4+ murine T cell hybridoma cells were used as the target cells. Hybridoma cells that were CD4- demonstrated no change in calcium or inositol-trisphosphate levels.
As a result of these studies we have identified a protein (LCF) as a natural ligand for the CD4 antigen, and have been able to classify CD4 as a growth factor receptor. The importance of an LCF-CD4 interaction may be as part of an amplification mechanism for recruiting and priming otherwise unresponsive cells to sites of inflammation.
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Dissertation (Ph.D.)--Boston University
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