The Effects of Imatinib Mesylate on Antigen-Specific Cd8+ T Cell Responses




Sinai, Parisa

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Imatinib mesylate (IM) is a chemical compound designed to inhibit the constitutive tyrosine kinase activity of the Bcr-Abl oncogene in Chronic Myelogenous Leukemia (CML). While IM is very potent in treating CML, little is understood concerning the effects of IM on the immune response. In this study, I have examined the influence of IM on antigen specific CD8 T cells. Mature OT-1 TCR transgenic T cells were transferred into B6.Thy1.1 recipients. This transfer was followed by an infection with Listeria monocytogenes (LM) expressing the cognate epitope OVA 257-264 (LM-OVA) to assess whether IM affects the specific CD8 T cell response generated to this intracellular pathogen. In vitro studies revealed that IM had no effect on proliferation, apoptosis, or IFN-gamma secretion of na?or memory OT-1 T cells at doses of =5muM, although at higher doses inhibition was observed. Adoptive transfer and in vivo infection studies demonstrated that in the presence of IM the primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered as measured by OT-1 T cell percentages in spleen and blood, their expression of IFN-gamma and their proliferation. However, IM influenced the primary OT-1 response by decreasing the expression of the IL-7Ralpha memory marker on OT-1 cells. IM treatment for >28 days resulted in a decreased percentage of OT-1 memory T cells before recall in blood. Furthermore, the response of memory OT-1 cells after LM-OVA rechallenge was diminished as measured by OT-1 T cell percentages in blood. In addition, IM treatment reduced the expression of IL-7Ralpha , a receptor required for memory cell survival, on effector and memory OT-1 cells. The function of memory OT-1 cells as measured by IFN-gamma expression was unaltered as was their proliferation as measured by incorporation of Brdu. Infection assays revealed that clearance of LM-OVA by memory mice is not altered by IM. In addition, the in vivo proliferation of memory OT-1 cells was not altered by IM. While IM did not alter the percentage of CD4 T cells in spleen and blood, IFN-gamma expression by CD4 T cells after recall was decreased. Together, these data demonstrate that IM reduces the number of OT-1 cells following a secondary challenge to an LM-OVA infection, and this may be a result of decreased IL-7Ralpha expression on effector and memory OT-1 cells.

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