Kraj, Piotr, Ph.D., D.V.M.
Member, Cancer Immunology, Inflammation & Tolerance
Associate Professor at the Center for Biotechnology and Genomic Medicine
GRU Cancer Center
Piotr Kraj, PhD, DVM is an Associate Professor at the Center for Biotechnology and Genomic Medicine and a member of the GRU Cancer Center. Dr. Kraj earned his PhD (1995) and a DVM (1987) in Poland.
Dr. Kraj studies the development and function of CD4+ T lymphocytes and mechanisms of immunological tolerance. A number of cellular, molecular and bioinformatics tools are used. The goal of this research is to uncover how tolerance mechanisms could be modulated to augment immune responses in cancer and control these responses in autoimmunity.
The discovery of regulatory T cells (TR) expressing transcription factor Foxp3 brought a new paradigm that immune tolerance is established and maintained by active suppression. Dr. Kraj investigates how thymic development of TR cells is regulated, what factors control maintenance and generation of TR cells in the periphery, and what is the mechanism of TR suppressor function.
To discriminate TR cells, a reporter mouse was produced that expresses green fluorescent protein controlled by the Foxp3 regulatory sequences and was used to show that the peripheral population of TR cells is heterogeneous and TR subsets differentially respond to antigenic stimulation with conventional and tumor-associated antigens. Comparison of the global gene expression profiles of conventional CD4+ T cells and TR cells identified genes that are TR cell-specific and that could be targeted to modulate TR cell function.
One of the genes identified is connexin 43, which controls TR cell suppressor function. By deleting connexin 43 in T cells, Dr. Kraj’s laboratory found that it controls Foxp3 expression and thymic generation of TR cells. The laboratory has generated a connexin 43 reporter mouse and are investigating ways to block the function of connexin 43 in TR cells.
The laboratory is also investigating how Bone Morphogenic Protein Receptor 1α (BMPR1α) signaling controls functions of conventional and TR cells. BMPR1α (Alk-3), expressed by activated effector and Foxp3+ regulatory CD4+ T cells (TR), modulates the functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the TGF-β family of cytokines, which also includes TGF-β and activins. BMPs play crucial roles in embryonic development, tissue differentiation and homeostasis, and development of cancer. It was demonstrated that BMPs and activins synergize with TGF-β to regulate thymic T cell development, and maintain TR cells and peripheral tolerance, but the precise mechanism of their function is not known.
Mice where BMPR1α is deleted in T cells (BMPR1αT- mice) had a decreased proportion of TR cells, and their T cells produced a higher level of IFN-γ and lower level of IL-4 than BMPR1α-sufficient cells when activated. The goal of this research is to understand how BMPR1α contributes to molecular signaling in activated conventional CD4+ and TR cells to regulate effector function and suppressor phenotype. The mechanism how BMPR1α controls TR cell homing into tumors is being investigated. Using BMPR1α inhibitors, the laboratory is testing how BMPR1α function can be blocked in normal T cells to augment anti-tumor immune response. This will establish if BMPR1α can be targeted to design new immunotherapies for cancer.
Funding for these projects come from an R01 grant from NCI and an R21 grant from NIAID.