Rao’s early research at Harvard was focused on
NFAT (Nuclear Factor of Activated T-cells) transcription factors, which she discovered with postdoctoral fellows Jugnu Jain and Pat McCaffrey and collaborator Patrick Hogan. They showed that NFAT proteins were expressed by most immune cells, and were essential for transcription of genes important for an immune response. They discovered that an inherited immunodeficiency was caused by a mutation in the gene encoding the CRAC channel
ORAI1. In the immunodeficient patients, the mutation in ORAI1 caused a complete loss of calcium entry and left the children susceptible to different kinds of infections. They showed that all three TET proteins are enzymes that alter gene expression by oxidizing the methyl group of the “fifth base”, 5-hydroxymethylcytosine, and causing
DNA demethylation, replacement of 5-methylcytosine by cytosine. At the La Jolla Institute, her lab demonstrated the importance of TET enzymes in proper gene expression, both in various cells of the immune system and during embryonic development. They also highlighted the role of TET proteins in suppressing cancer development, particularly in lymphoid, myeloid and other hematological malignancies, As a continuation of their longstanding interest in NFAT and calcium signalling, Rao and Hogan have also performed research on T cell exhaustion. With colleagues, they worked to define the term
T cell exhaustion, which was vaguely used to mean decreased immune responses due to overstimulation of T-cells by antigens. Their research specifically focuses on T cells found within tumors. They and their colleagues have shown that like normal T cells,
T cells with Chimeric Antigen Receptors (CAR) become exhausted when residing in a tumor. They concluded that
TOX and
NR4A transcription factors play an important role in the exhaustion of T cells, and that inhibition or disruption of these transcription factors is a promising approach for cancer immunotherapy. == References ==