Timothy N. Bullock, PhD

Timothy N. Bullock, PhD

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Role of CD4 T cells in promoting CD8 T cell anti-tumor immunity

The Bullock laboratory examines cellular immunity to cancer with a focus on understanding the interactions between the dendritic cells that are responsible for initiating immune responses and tumor-specific CD4+ T cells, which support the expansion of immune responses.  A first area of focus is defining the specificity and function of CD4+ T cells that target tyrosinase, which is a protein expressed by melanoma cells that is often targeted by the immune response in melanoma patients.  Using antibodies produced in the Hybridoma core and a unique transgenic mouse model, they have shown that tyrosinase-specific CD4+ T cells contribute to the expansion of both naïve and memory tyrosinase-specific CD8+ T cells in response to tumor challenge.  Using mammalian and bacterial expression systems, produced with the help of the DNA and Protein Science cores, the lab is currently defining the exact sequences within tyrosinase that the CD4+ T cells are responding to with the intent of incorporating them into dendritic cell-based vaccines.

Further studies into the interaction between CD4+ T cells and dendritic cells have revealed that the requirement for CD4+ T cells for effective dendritic cell-based vaccines can be overcome by stimulating the dendritic cells with CD40L.  Flow cytometric analyses of CD40L-stimulated DC, performed in the Flow cytometry facility, revealed that the upregulation of CD70 substantially contributes to the immunogenicity of CD40L-stimulated dendritic cells.  Currently, using the transgenic core facility, the lab is generating a conditional CD70-knockout that will allow a clear delineation of the contribution of CD70 to T cell responses.  In addition, the lab is beginning to examine the capacity of dendritic cells derived from tumor biopsies and tumor draining nodes to express CD70 and other members of the TNF superfamily.  These studies are being performed in collaboration with Dr Craig Slingluff and will utilize the Tissue Procurement and Research Histology cores.