Our laboratory studies the cellular and molecular mechanisms involved in the requirements for the generation of distinct T lymphocyte lineages. Along with gene transfer technology, we use this knowledge to generate polyfunctional T-cells that mediate potent responses against established tumors. Our studies on costimulatory molecules CD28 and ICOS are focused on how they differentiate towards either the helper or cytotoxic lineages. We are characterizing the transcription factors involved in lineage commitment, plasticity and in regulation of CD4 and CD8 gene expression, with emphasis on the roles of RORC, Tbet, GATA3, and FoxP3 and the mechanisms for establishing epigenetic programs in maturing tumor-specific T cell subsets. Our studies on both mouse and human T cells have led to the discovery of a costimulatory molecule, the inducible costimulatory molecule ICOS, that is required for the differentiation of highly inflammatory Th17 cells. We are investigating how ICOS signaling and interactions between transcription factors influence T helper cell differentiation towards the Th17 versus the anti-inflammatory regulatory T cell lineages in an adoptive cell transfer mouse and human models of cancer.
Another distinct area of interest of our laboratory is in elucidating the mechanisms by which chemotherapy and or total body irradiation is effective in improving T-cell based immunotherapies. We are employing genetic and cell biological approaches to study the mechanism for enhancement of mouse and human Tumor-specific T cell function and proliferation by host preconditioning. We are also developing mouse models to study the potential role of these genetically redirected cells in optimally preconditioned mice.
ICOS sends the right signals to human Th17 cells to break self-tolerance to tumors.
Paulos, CM et. al., Science Transl Med. 2 (55):55ra78 (2010)